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Characterization of Proprotein Convertases and Their Involvement in Virus Propagation

  • Wolfgang Garten
Chapter

Abstract

Proprotein convertases (PCs), also known as eukaryotic subtilases, are a group of serine proteases comprising furin (PACE), PC1 (PC3), PC2, PC4, PACE4, PC5 (PC6), and PC7 (LPC, PC8) that generate bioactive proteins and peptides, such as hormones, receptors, and growth factors by cleaving precursor proteins at multibasic motifs. Two other family members, SKI-1/S1P and PCSK9, cleave regulator proteins involved in cholesterol and fatty acid homeostasis at nonbasic peptide bonds. Furin is ubiquitous in eukaryotic tissues and cells. PACE4, PC5, and PC7 are also widespread, whereas the expression of the other PCs is more restricted. PCs are synthesized as multi-segmented zymogens which are autocatalytically activated. The prodomains have regulatory and inhibitory functions. The catalytic domains are the most conserved domains among the PCs. The architecture of the catalytic active furin domain is known in different binding states. The C-terminal parts of the PCs differ in length and structure and contain encoded peptide signatures guiding the PCs to the subcellular destinations on the secretory pathways: SKI-1/S1P to the cis-Golgi, furin, PC5B, and PC7 to the TGN region but also to the plasma membrane. PACE4, PC5A, and PCSK9 are attached at the cell surface. Truncated, soluble furin and SKI-1/S1P, as well as PC1 and PC2, are released into the extracellular matrix. Many enveloped viruses are activated by furin and furin-like PCs and arenaviruses and a few bunyaviruses by SKI-1/S1P. The PCs cleave the viral fusion glycoprotein to trigger fusion of viral envelopes with cellular membranes to deliver the viral genome into host cells. Cleavage by PCs, occasionally in concert with other endoproteases, enables conformational changes in the viral membrane proteins needed for correct oligomerization of glycoprotein spikes and their effective incorporation into virions. Mutational alterations of PC cleavage sites can reduce the fusion potential of viral surface proteins and thus facilitate the development of secure live attenuated vaccines. Alternatively, agents preventing cleavage of viral surface (glyco)proteins block fusion capacity and multicyclic virus replications. PC inhibitors are suggested as promising antiviral drugs for quite a number of viruses causing severe infections.

Keywords

Furin PC1/3 PC2 PACE4 PC5/6 PC7/8 SKI-1/S1P Subcellular localization and trafficking PCs structure and biosynthesis Fusion proteins Biologically active peptides Glycoprotein trimerization and incorporation Protease activation mutants 

References

  1. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6.PubMedCrossRefGoogle Scholar
  2. Seidah NG, Abifadel M, Prost S, Boileau C, Prat A. The proprotein convertases in hypercholesterolemia and cardiovascular diseases: emphasis on Proprotein Convertase Subtilisin/Kexin 9. Pharmacol Rev. 2017;69(1):33–52. Review.PubMedCrossRefGoogle Scholar
  3. Achstetter T, Wolf DH. Hormone processing and membrane-bound proteinases in yeast. EMBO J. 1985;4(1):173–1.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Allison LMC, Salter MWAP, Kiguwa S, Howard CR. Analysis of the glycoprotein gene of Tacaribe virus and neutralization-resistant variants. J Gen Virol. 1991;72:2025–9.PubMedCrossRefGoogle Scholar
  5. Altamura LA, Bertolotti-Ciarlet A, Teigler J, Paragas J, Schmaljohn CS, Doms RW. Identification of a novel C-terminal cleavage of Crimean-Congo hemorrhagic fever virus PreGN that leads to generation of an NSM protein. J Virol. 2007;81(12):6632–42.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F. Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 2001;15(10):1837–9.PubMedCrossRefGoogle Scholar
  7. Anderson ED, Thomas L, Hayflick JS, Thomas G. Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed alpha 1-antitrypsin variant. J Biol Chem. 1993;268(33):24887–91.PubMedPubMedCentralGoogle Scholar
  8. Anderson ED, VanSlyke JK, Thulin CD, Jean F, Thomas G. Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage. EMBO J. 1997;16(7):1508–18.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Artenstein AW, Opal SM. Proprotein convertases in health and disease. N Engl J Med. 2011;365(26):2507–18. Review.PubMedCrossRefGoogle Scholar
  10. Assadi M, Sharpe JC, Snell C, Loh YP. The C-terminus of prohormone convertase 2 is sufficient and necessary for Raft association and sorting to the regulated secretory pathway. Biochemistry. 2004;43(24):7798–807.PubMedCrossRefGoogle Scholar
  11. Barr PJ. Mammalian subtilisins: the long-sought dibasic processing endoproteases. Cell. 1991;66(1):1–3. Review.PubMedCrossRefGoogle Scholar
  12. Basak A, Touré BB, Lazure C, Mbikay M, Chrétien M, Seidah NG. Enzymic characterization in vitro of recombinant proprotein convertase PC4. Biochem J. 1999;343(Pt 1):29–37.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Basak A, Mitra A, Basak S, Pasko C, Chrétien M, Seaton P. A fluorogenic peptide containing the processing site of human SARS corona virus S-protein: kinetic evaluation and NMR structure elucidation. ChemBioChem. 2007;8(9):1029–37.PubMedCrossRefGoogle Scholar
  14. Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A. 2009;106(14):5871–6.  https://doi.org/10.1073/pnas.0809524106. Epub 2009 Mar 24.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bergeron É, Zivcec M, Chakrabarti AK, Nichol ST, Albariño CG, Spiropoulou CF. Recovery of recombinant Crimean Congo hemorrhagic fever virus reveals a function for non-structural glycoproteins cleavage by Furin. PLoS Pathog. 2015;11(5):e1004879.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Beyer WR, Pöpplau D, Garten W, von Laer D, Lenz O. Endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase SKI-1/S1P. Virology. 2003;77(5):2866–72.CrossRefGoogle Scholar
  17. Bhattacharjya S, Xu P, Zhong M, Chrétien M, Seidah NG, Ni F. Inhibitory activity and structural characterization of a C-terminal peptide fragment derived from the prosegment of the proprotein convertase PC7. Biochemistry. 2000;39(11):2868–77.PubMedCrossRefGoogle Scholar
  18. Bodvard K, Mohlin J, Knecht W. Recombinant expression, purification, and kinetic and inhibitor characterisation of human site-1-protease. Protein Expr Purif. 2007;51(2):308–19.PubMedCrossRefGoogle Scholar
  19. Bosch FX, Garten W, Klenk HD, Rott R. Proteolytic cleavage of influenza virus hemagglutinins: primary structure of the connecting peptide between HA1 and HA2 determines proteolytic cleavability and pathogenicity of Avian influenza viruses. Virology. 1981;113(2):725–35.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Bosch BJ, Bartelink W, Rottier PJ. Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide. J Virol. 2008;82(17):8887–90.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bosshart H, Humphrey J, Deignan E, Davidson J, Drazba J, Yuan L, Oorschot V, Peters PJ, Bonifacino JS. The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system. J Cell Biol. 1994;126(5):1157–72.PubMedCrossRefGoogle Scholar
  22. Böttcher-Friebertshäuser E, Garten W, Matrosovich M, Klenk HD. The hemagglutinin: a determinant of pathogenicity. Curr Top Microbiol Immunol. 2014;385:3–34. Review.PubMedGoogle Scholar
  23. Braks JA, Martens GJ. 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway. Cell. 1994;78(2):263–73.PubMedCrossRefGoogle Scholar
  24. Bresnahan PA, Leduc R, Thomas L, Thorner J, Gibson HL, Brake AJ, Barr PJ, Thomas G. Human fur gene encodes a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo. J Cell Biol. 1990;111(6 Pt 2):2851–9.PubMedCrossRefGoogle Scholar
  25. Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A. 1999;96(20):11041–8. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Brücher KH, Garten W, Klenk HD, Shaw E, Radsak K. Inhibition of endoproteolytic cleavage of cytomegalovirus (HCMV) glycoprotein B by palmitoyl-peptidyl-chloromethyl ketone. Virology. 1990;178(2):617–20.PubMedCrossRefGoogle Scholar
  27. Bruzzaniti A, Goodge K, Jay P, Taviaux SA, Lam MH, Berta P, Martin TJ, Moseley JM, Gillespie MT. PC8 [corrected], a new member of the convertase family. Biochem J. 1996;314(Pt 3):727–31.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Burri DJ, Pasqual G, Rochat C, Seidah NG, Pasquato A, Kunz S. Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease. J Virol. 2012;86(9):4935–46.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Burri DJ, da Palma JR, Kunz S, Pasquato A. Envelope glycoprotein of arenaviruses. Virus. 2012;4(10):2162–81.CrossRefGoogle Scholar
  30. Burri DJ, da Palma JR, Seidah NG, Zanotti G, Cendron L, Pasquato A, Kunz S. Differential recognition of Old World and New World arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). J Virol. 2013;87(11):6406–14.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Cameron A, Appel J, Houghten RA, Lindberg I. Polyarginines are potent furin inhibitors. Biol Chem. 2000;275(47):36741–9.CrossRefGoogle Scholar
  32. Canaff L, Bennett HP, Hou Y, Seidah NG, Hendy GN. Proparathyroid hormone processing by the proprotein convertase-7: comparison with furin and assessment of modulation of parathyroid convertase messenger ribonucleic acid levels by calcium and 1,25-dihydroxyvitamin D3. Endocrinology. 1999;140(8):3633–42.PubMedCrossRefGoogle Scholar
  33. Cavanagh D, Davis PJ, Pappin DJ, Binns MM, Boursnell ME, Brown TD. Coronavirus IBV: partial amino terminal sequencing of spike polypeptide S2 identifies the sequence Arg-Arg-Phe-Arg-Arg at the cleavage site of the spike precursor propolypeptide of IBV strains Beaudette and M41. Virus Res. 1986;4(2):133–43.PubMedCrossRefGoogle Scholar
  34. Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science. 2005;308(5728):1643–5.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Cieplik M, Klenk HD, Garten W. Identification and characterization of spodoptera frugiperda furin: a thermostable subtilisin-like endopeptidase. Biol Chem. 1998;379(12):1433–40.PubMedCrossRefGoogle Scholar
  36. Constam DB, Calfon M, Robertson EJ. SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. J Cell Biol. 1996;134(1):181–91.PubMedCrossRefGoogle Scholar
  37. Creemers JW, Khatib AM. Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front Biosci. 2008;13:4960–71. Review.PubMedCrossRefGoogle Scholar
  38. Creemers JW, Vey M, Schäfer W, Ayoubi TA, Roebroek AJ, Klenk HD, Garten W, Van de Ven WJ. Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. J Biol Chem. 1995;270(6):2695–70.PubMedCrossRefGoogle Scholar
  39. Creemers JWM, Usac EF, Bright NA, Van de Loo JW, Jansen E, Van de Ven WJM, Hutton JC. Identification of a transferable sorting domain for the regulated pathway in the prohormone convertase PC2. J Biol Chem. 1996;271:25284–91.PubMedCrossRefGoogle Scholar
  40. Creemers JW, van de Loo JW, Plets E, Hendershot LM, Van De Ven WJ. Binding of BiP to the processing enzyme lymphoma proprotein convertase prevents aggregation, but slows down maturation. J Biol Chem. 2000;275(49):38842–7.PubMedCrossRefGoogle Scholar
  41. Creemers JW, Pritchard LE, Gyte A, Le Rouzic P, Meulemans S, Wardlaw SL, Zhu X, Steiner DF, Davies N, Armstrong D, Lawrence CB, Luckman SM, Schmitz CA, Davies RA, Brennand JC, White A. Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology. 2006;147(4):1621–31.PubMedCrossRefGoogle Scholar
  42. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol. 2007;14:413–9.PubMedCrossRefGoogle Scholar
  43. da Palma JR, Burri DJ, Oppliger J, Salamina M, Cendron L, de Laureto PP, Seidah NG, Kunz S, Pasquato A. Zymogen activation and subcellular activity of subtilisin kexin isozyme 1/site 1 protease. J Biol Chem. 2014;289:35743–56.PubMedPubMedCentralCrossRefGoogle Scholar
  44. da Palma JR, Cendron L, Seidah NG, Pasquato A, Kunz S. Mechanism of folding and activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P). J Biol Chem. 2016;291(5):2055–66.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Dahms SO, Hardes K, Becker GL, Steinmetzer T, Brandstetter H, Than ME. X-ray structures of human furin in complex with competitive inhibitors. ACS Chem Biol. 2014;9(5):1113–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Dahms SO, Creemers JW, Schaub Y, Bourenkov GP, Zögg T, Brandstetter H, Than ME. The structure of a furin-antibody complex explains non-competitive inhibition by steric exclusion of substrate conformers. Sci Rep. 2016;6:34303.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Dahms SO, Arciniega M, Steinmetzer T, Huber R, Than ME. Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proc Natl Acad Sci U S A. 2016;113(40):11196–201.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Dahms SO, Jiao GS, Than ME. Structural studies revealed active site distortions of human furin by a small molecule inhibitor. ACS Chem Biol. 2017.Google Scholar
  49. Day PM, Lowy DR, Schiller JT. Heparan sulfate-independent cell binding and infection with furin-precleaved papillomavirus capsids. J Virol. 2008;82(24):12565–8.PubMedPubMedCentralCrossRefGoogle Scholar
  50. De Bie I, Savaria D, Roebroek AJ, Day R, Lazure C, Van de Ven WJ, Seidah NG. Processing specificity and biosynthesis of the Drosophila melanogaster convertases dfurin1, dfurin1-CRR, dfurin1-X, and dfurin2. J Biol Chem. 1995;270(3):1020–8.PubMedCrossRefGoogle Scholar
  51. De Bie I, Marcinkiewicz M, Malide D, Lazure C, Nakyama K, Bendayan M, Seidah NG. The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. sorting signals YxxL, LL und acidic serine-casein kinase phosphorylation, PC5, PC7, kexin, furin. J Cell Biol. 1996;135:1261–75.PubMedCrossRefGoogle Scholar
  52. de Haan CA, Stadler K, Godeke GJ, Bosch BJ, Rottier PJ. Cleavage inhibition of the murine coronavirus spike protein by a furin-like enzyme affects cell-cell but not virus-cell fusion. J Virol. 2004;78(11):6048–54.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Declercq J, Meulemans S, Plets E, Creemers JW. I nternalization of proprotein convertase PC7 from plasma membrane is mediated by a novel motif. J Biol Chem. 2012;287(12):9052–60.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Declercq J, Ramos-Molina B, Sannerud R, Brouwers B, Pruniau VPEG, Meulemans S, Plets E, Annaert W, Creemers JWM. Endosome to trans-Golgi network transport of Proprotein Convertase 7 is mediated by a cluster of basic amino acids and palmitoylated cysteines. Eur J Cell Biol. 2017. pii: S0171-9335(16)30198-4.Google Scholar
  55. Decroly E, Benjannet S, Savaria D, Seidah NG. Comparative functional role of PC7 and furin in the processing of the HIV envelope glycoprotein gp160. FEBS Lett. 1997;405(1):68–72.PubMedCrossRefGoogle Scholar
  56. Dikeakos JD, Di Lello P, Lacombe MJ, Ghirlando R, Legault P, Reudelhuber TL, Omichinski JG. Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease. Proc Natl Acad Sci U S A. 2009;106(18):7408–13.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Dillon SL, Williamson DM, Elferich J, Radler D, Joshi R, Thomas G, Shinde U. Propeptides are sufficient to regulate organelle-specific pH-dependent activation of furin and proprotein convertase 1/3. J Mol Biol. 2012;423(1):47–62.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Duda A, Stange A, Lüftenegger D, Stanke N, Westphal D, Pietschmann T, Eastman SW, Linial ML, Rethwilm A, Lindemann D. Prototype foamy virus envelope glycoprotein leader peptide processing is mediated by a furin-like cellular protease, but cleavage is not essential for viral infectivity. J Virol. 2004;78(24):13865–70.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Duguay SJ, Lai-Zhang J, Steiner DF. Mutational analysis of the insulin-like growth factor I prohormone processing site. J Biol Chem. 1995;270(29):17566–74.PubMedCrossRefGoogle Scholar
  60. Eichler R, Lenz O, Garten W, Strecker T. The role of single N-glycans in proteolytic processing and cell surface transport of the Lassa virus glycoprotein GP-C. Virol J. 2006;3:41.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Eickmann M, Kiermayer S, Kraus I, Gössl M, Richt JA, Garten W. Maturation of Borna disease virus glycoprotein. FEBS Lett. 2005;579(21):4751–6.PubMedCrossRefGoogle Scholar
  62. Eisenberg RJ, Atanasiu D, Cairns TM, Gallagher JR, Krummenacher C, Cohen GH. Herpes virus fusion and entry: a story with many characters. Virus. 2012;4(5):800–32. Review.CrossRefGoogle Scholar
  63. Elagoz A, Benjannet S, Mammarbassi A, Wickham L, Seidah NG. Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. J Biol Chem. 2002;277(13):11265–75.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Elshuber S, Allison SL, Heinz FX, Mandl CW. Cleavage of protein prM is necessary for infection of BHK-21 cells by tick-borne encephalitis virus. J Gen Virol. 2003;84(Pt 1):183–91.PubMedCrossRefGoogle Scholar
  65. Essalmani R, Zaid A, Marcinkiewicz J, Chamberland A, Pasquato A, Seidah NG, Prat A. In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate. Proc Natl Acad Sci U S A. 2008;105(15):5750–5.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Essalmani R, Susan-Resiga D, Guillemot J, Kim W, Sachan V, Awan Z, Chamberland A, Asselin MC, Ly K, Desjardins R, Day R, Prat A, Seidah NG. Thrombin activation of protein C requires prior processing by a liver proprotein convertase. J Biol Chem. 2017;292(25):10564–73.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, Keogh J, O’Rahilly S, Creemers JW. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab. 2007;92(9):3369–73.PubMedCrossRefGoogle Scholar
  68. Feldmann A, Schäfer MK, Garten W, Klenk HD. Targeted infection of endothelial cells by avian influenza virus A/FPV/Rostock/34 (H7N1) in chicken embryos. J Virol. 2000;74(17):8018–27.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Follis KE, York J, Nunberg JH. Furin cleavage of the SARS coronavirus spike glycoprotein enhances cell-cell fusion but does not affect virion entry. Virology. 2006;350(2):358–69.PubMedCrossRefGoogle Scholar
  70. Fujii Y, Sakaguchi T, Kiyotani K, Yoshida T. Comparison of substrate specificities against the fusion glycoprotein of virulent Newcastle disease virus between a chick embryo fibroblast processing protease and mammalian subtilisin-like proteases. Microbiol Immunol. 1999;43(2):133–40.PubMedCrossRefGoogle Scholar
  71. Fuller RS, Brake A, Thorner J. Yeast prohormone processing enzyme (KEX2 gene product) is a Ca2+-dependent serine protease. Proc Natl Acad Sci U S A. 1989a;86(5):1434–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Fuller RS, Brake AJ, Thorner J. Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science. 1989b;246(4929):482–6.PubMedCrossRefGoogle Scholar
  73. Gabriel G, Garn H, Wegmann M, Renz H, Herwig A, Klenk HD, Stech J. The potential of a protease activation mutant of a highly pathogenic avian influenza virus for a pandemic live vaccine. Vaccine. 2008;26(7):956–65.PubMedCrossRefGoogle Scholar
  74. Garred O, van Deurs B, Sandvig K. Furin-induced cleavage and activation of Shiga toxin. J Biol Chem. 1995;270(18):10817–21.PubMedCrossRefGoogle Scholar
  75. Garten W, Bosch FX, Linder D, Rott R, Klenk HD. Proteolytic activation of the influenza virus hemagglutinin: The structure of the cleavage site and the enzymes involved in cleavage. Virology. 1981;115(2):361–74.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Garten W, Linder D, Rott R, Klenk HD. The cleavage site of the hemagglutinin of fowl plague virus. Virology. 1982;122(1):186–90.PubMedCrossRefGoogle Scholar
  77. Garten W, Kuroda K, Schuy W, Naruse H, Scholtissek C, Klenk HD. Haemagglutinin transport mutants. Vaccine. 1985;3(3 Suppl):227–9.PubMedCrossRefGoogle Scholar
  78. Garten W, Stieneke A, Shaw E, Wikstrom P, Klenk HD. Inhibition of proteolytic activation of influenza virus hemagglutinin by specific peptidyl chloroalkyl ketones. Virology. 1989;172(1):25–31.PubMedCrossRefGoogle Scholar
  79. Garten W, Vey M, Ohuchi R, Ohuchi M, Klenk HD. Modification of the cleavage activation of the influenza virus hemagglutinin by site-specific mutagenesis. Behring Inst Mitt. 1991;89:12–22.Google Scholar
  80. Garten W, Hallenberger S, Ortmann D, Schäfer W, Vey M, Angliker H, Shaw E, Klenk HD. Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidyl chloroalkyl ketones. Biochimie. 1994;76(3-4):217–25. ReviewPubMedCrossRefGoogle Scholar
  81. Garten W, Braden C, Arendt A, Peitsch C, Baron J, Lu Y, Pawletko K, Hardes K, Steinmetzer T, Böttcher-Friebertshäuser E. Influenza virus activating host proteases: identification, localization and inhibitors as potential therapeutics. Eur J Cell Biol. 2015;94(7-9):375–83.PubMedCrossRefGoogle Scholar
  82. Geiselhart V, Bastone P, Kempf T, Schnölzer M, Löchelt M. Furin-mediated cleavage of the feline foamy virus. J Virol. 2004;78(24):13573–81.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Gil-Torregrosa BC, Castano AR, Lopez D, Del Val M. Generation of MHC class I peptide antigens by protein processing in the secretory route by furin. Traffic. 2000;1:641–51.PubMedCrossRefGoogle Scholar
  84. González-Reyes L, Ruiz-Argüello MB, García-Barreno B, Calder L, López JA, Albar JP, Skehel JJ, Wiley DC, Melero JA. Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci U S A. 2001;98(17):9859–64.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Gordon VM, Leppla SH. Proteolytic activation of bacterial toxins: role of bacterial and host cell proteases. Infect Immun. 1994;62(2):333–40. Review.PubMedPubMedCentralGoogle Scholar
  86. Gordon VM, Rehemtulla A, Leppla SH. A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen. Infect Immun. 1997;65(8):3370–5.PubMedPubMedCentralGoogle Scholar
  87. Gorski JP, Huffman NT, Chittur S, Midura RJ, Black C, Oxford J, Seidah NG. Inhibition of proprotein convertase SKI-1 blocks transcription of key extracellular matrix genes regulating osteoblastic mineralization. J Biol Chem. 2011;286(3):1836–49.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Gotoh B, Ohnishi Y, Inocencio NM, Esaki E, Nakayama K, Barr PJ, Thomas G, Nagai Y. Mammalian subtilisin-related proteinases in cleavage activation of the paramyxovirus fusion glycoprotein: superiority of furin/PACE to PC2 or PC1/PC3. J Virol. 1992;66(11):6391–7.PubMedPubMedCentralGoogle Scholar
  89. Gu M, Rappaport J, Leppla SH. Furin is important but not essential for the proteolytic maturation of gp160 of HIV-1. FEBS Lett. 1995;365(1):95–7.PubMedCrossRefGoogle Scholar
  90. Guillemot J, Canuel M, Essalmani R, Prat A, Seidah NG. Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin. Hepatology. 2013;57(6):2514–24.PubMedCrossRefGoogle Scholar
  91. Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature. 1992;360(6402):358–61.PubMedCrossRefGoogle Scholar
  92. Hallenberger S, Moulard M, Sordel M, Klenk HD, Garten W. The role of eukaryotic subtilisin-like endoproteases for the activation of human immunodeficiency virus glycoproteins in natural host cells. J Virol. 1997;71(2):1036–45.PubMedPubMedCentralGoogle Scholar
  93. Hardes K, Becker GL, Lu Y, Dahms SO, Köhler S, Beyer W, Sandvig K, Yamamoto H, Lindberg I, Walz L, von Messling V, Than ME, Garten W, Steinmetzer T. Novel Furin inhibitors with potent anti-infectious activity. ChemMedChem. 2015;10(7):1218–31.PubMedCrossRefGoogle Scholar
  94. Hardes K, Ivanova T, Thaa B, McInermey GM, Klokk TI, Sandvig K, Kunzel S, Lindberg I, Steinmetzer T. Elongated and shortened peptidomimetic inhibitors of the proprotein convertase furin. ChemMedChem. 2017;12:613–20.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Harrison SC. Viral membrane fusion. Nat Struct Mol Biol. 2008;15(7):690–8.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Hatsuzawa K, Hosaka M, Nakagawa T, Nagase M, Shoda A, Murakami K, Nakayama K. Structure and expression of mouse furin, a yeast Kex2-related protease. Lack of processing of coexpressed prorenin in GH4C1 cells. J Biol Chem. 1990;265(36):22075–8.PubMedGoogle Scholar
  97. Heidner HW, Johnston RE. The amino-terminal residue of Sindbis virus glycoprotein E2 influences virus maturation, specific infectivity for BHK cells, and virulence in mice. J Virol. 1994;68(12):8064–70.PubMedPubMedCentralGoogle Scholar
  98. Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG. Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study. J Biol Chem. 1995;270(16):9517–25.PubMedCrossRefGoogle Scholar
  99. Henrich S, Cameron A, Bourenkov GP, Kiefersauer R, Huber R, Lindberg I, Bode W, Than ME. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol. 2003;10(7):520–6. PDB: 1PJ8. Erratum in: Nat Struct Biol. 2003;10(8):669.PubMedCrossRefGoogle Scholar
  100. Henrich S, Lindberg I, Bode W, Than ME. Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J Mol Biol. 2005;345(2):211–27.PubMedCrossRefGoogle Scholar
  101. Himmelspach M, Pfleiderer M, Fischer BE, Plaimauer B, Antoine G, Falkner FG, Dorner F, Schlokat U. Recombinant human factor X: high yield expression and the role of furin in proteolytic maturation in vivo and in vitro. Thromb Res. 2000;97(2):51–67.PubMedCrossRefGoogle Scholar
  102. Horimoto T, Kawaoka Y. The hemagglutinin cleavability of a virulent avian influenza virus by subtilisin-like endoproteases is influenced by the amino acid immediately downstream of the cleavage site. Virology. 1995;210(2):466–70.PubMedCrossRefGoogle Scholar
  103. Horimoto T, Nakayama K, Smeekens SP, Kawaoka Y. Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses. J Virol. 1994;68(9):6074–8.PubMedPubMedCentralGoogle Scholar
  104. Ito K, Kim KH, Lok AS, Tong S. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol. 2009;83(8):3507–17.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Jain SK, De Candido S, Kielian M. Processing of the p62 envelope precursor protein of Semliki Forest virus. J Biol Chem. 1991;266(9):5756–61.PubMedPubMedCentralGoogle Scholar
  106. Jardetzky TS, Lamb RA. Activation of paramyxovirus membrane fusion and virus entry. Curr Opin Virol. 2014;5:24–33. Review.PubMedCrossRefGoogle Scholar
  107. Jean F, Stella K, Thomas L, Liu G, Xiang Y, Reason AJ, Thomas G. alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci U S A. 1998;95(13):7293–8.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E. Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci U S A. 2004;101(46):16286–91.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Julius D, Brake A, Blair L, Kunisawa R, Thorner J. Isolation of the putative structural gene for the lysine-arginine cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell. 1984;37:1075–89.PubMedCrossRefGoogle Scholar
  110. Kacprzak MM, Peinado JR, Than ME, Appel J, Henrich S, Lipkind G, Houghten RA, Bode W, Lindberg I. Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine. J Biol Chem. 2004;279(35):36788–94.PubMedCrossRefGoogle Scholar
  111. Kawaoka Y, Webster RG. Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A. 1988;85(2):324–8.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Kawaoka Y, Nestorowicz A, Alexander DJ, Webster RG. Molecular analyses of the hemagglutinin genes of H5 influenza viruses: origin of a virulent turkey strain. Virology. 1987;158(1):218–27.PubMedCrossRefGoogle Scholar
  113. Keelapang P, Sriburi R, Supasa S, Panyadee N, Songjaeng A, Jairungsri A, Puttikhunt C, Kasinrerk W, Malasit P, Sittisombut N. Alterations of pr-M cleavage and virus export in pr-M junction chimeric dengue viruses. J Virol. 2004;78(5):2367–81.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Kemmler W, Peterson JD, Steiner DF. Studies on the conversion of proinsulin to insulin. I. Conversion in vitro with trypsin and carboxypeptidase B. J Biol Chem. 1971;246(22):6786–91.PubMedPubMedCentralGoogle Scholar
  115. Khatib AM, Siegfried G, Prat A, Luis J, Chrétien M, Metrakos P, Seidah NG. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions. J Biol Chem. 2001;276(33):30686–93.PubMedCrossRefGoogle Scholar
  116. Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ. Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15. DNA Cell Biol. 1991;10(10):757–69.PubMedCrossRefGoogle Scholar
  117. Klenk HD, Garten W. Activation cleavage of viral spike proteins by host proteases. In: Wimmer E, editor. Cellular receptors for animal viruses. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1994. p. 241–80.Google Scholar
  118. Klenk HD, Garten W, Rott R. Inhibition of proteolytic cleavage of the hemagglutinin of influenza virus by the calcium-specific ionophore A23187. EMBO J. 1984;3(12):2911–5.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Kopp A, Blewett E, Misra V, Mettenleiter TC. Proteolytic cleavage of bovine herpesvirus 1 (BHV-1) glycoprotein gB is not necessary for its function in BHV-1 or pseudorabies virus. J Virol. 1994;68(3):1667–74.PubMedPubMedCentralGoogle Scholar
  120. Kouretova J, Hammamy MZ, Epp A, Hardes K, Kallis S, Zhang L, Hilgenfeld R, Bartenschlager R, Steinmetzer T. Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication. J Enzyme Inhib Med Chem. 2017;32(1):712–21.PubMedCrossRefGoogle Scholar
  121. Kuno G, Chang GJ. Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses. Arch Virol. 2007;152(4):687–96.PubMedCrossRefGoogle Scholar
  122. Kunz S, Edelmann KH, de la Torre JC, Gorney R, Oldstone MB. Mechanisms for lymphocytic choriomeningitis virus glycoprotein cleavage, transport, and incorporation into virions. Virology. 2003;314(1):168–78.CrossRefPubMedPubMedCentralGoogle Scholar
  123. Kuroda K, Hauser C, Rott R, Klenk HD, Doerfler W. Expression of the influenza virus haemagglutinin in insect cells by a baculovirus vector. EMBO J. 1986;5(6):1359–65.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Kuroda K, Gröner A, Frese K, Drenckhahn D, Hauser C, Rott R, Doerfler W, Klenk HD. Synthesis of biologically active influenza virus hemagglutinin in insect larvae. J Virol. 1989;63(4):1677–85.PubMedPubMedCentralGoogle Scholar
  125. Le QT, Blanchet M, Seidah NG, Labonté P. Plasma Membrane Tetraspanin CD81 complexes with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and low density lipoprotein receptor (LDLR), and its levels are reduced by PCSK9. J Biol Chem. 2015;290(38):23385–400.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Leduc R, Molloy SS, Thorne BA, Thomas G. Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. J Biol Chem. 1992;267(20):14304–8.PubMedPubMedCentralGoogle Scholar
  127. Lee SN, Lindberg I. 7B2 prevents unfolding and aggregation of prohormone convertase. Endocrinology. 2008;149(8):4116–27.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Lee SN, Lee DH, Lee MG, Yoon JH. Proprotein convertase 5/6a is associated with bone morphogenetic protein-2-induced squamous cell differentiation. Am J Respir Cell Mol Biol. 2015;52(6):749–61.PubMedCrossRefGoogle Scholar
  129. Lenz O, ter Meulen J, Feldmann H, Klenk HD, Garten W. Identification of a novel consensus sequence at the cleavage site of the Lassa virus glycoprotein. J Virol. 2000;74(23):11418–21.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Lenz O, ter Meulen J, Klenk HD, Seidah NG, Garten W. The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc Natl Acad Sci U S A. 2001;98(22):12701–5. Epub 2001 Oct 16.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Li S, Sun Z, Pryce R, Parsy ML, Fehling SK, Schlie K, Siebert CA, Garten W, Bowden TA, Strecker T, Huiskonen JT. Acidic pH-induced conformations and LAMP1 binding of the Lassa Virus glycoprotein spike. PLoS Pathog. 2016;12(2):e1005418.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Long G, Pan X, Westenberg M, Vlak JM. Functional role of the cytoplasmic tail domain of the major envelope fusion protein of group II baculoviruses. J Virol. 2006;80(22):11226–34.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Longpré JM, Leduc R. Identification of prodomain determinants involved in ADAMTS-1 biosynthesis. J Biol Chem. 2004;279(32):33237–45.PubMedCrossRefGoogle Scholar
  134. Lopez-Perez E, Zhang Y, Frank SJ, Creemers J, Seidah N, Checler F. Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J Neurochem. 2001;76(5):1532–9.PubMedCrossRefGoogle Scholar
  135. Lu Y, Hardes K, Dahms SO, Böttcher-Friebertshäuser E, Steinmetzer T, Than ME, Klenk HD, Garten W. Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells. Antiviral Res. 2015;120:89–100.PubMedCrossRefGoogle Scholar
  136. Lusson J, Vieau D, Hamelin J, Day R, Chrétien M, Seidah NG. cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proc Natl Acad Sci U S A. 1993;90(14):6691–5.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Mains RE, Berard CA, Denault JB, Zhou A, Johnson RC, Leduc R. PACE4: a subtilisin-like endoprotease with unique properties. Biochem J. 1997;321(Pt 3):587–93.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Maisa A, Ströher U, Klenk HD, Garten W, Strecker T. Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1)-antitrypsin variants. PLoS Negl Trop Dis. 2009;3(6):e446.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Mbikay M, Tadros H, Ishida N, Lerner CP, De Lamirande E, Chen A, El-Alfy M, Clermont Y, Seidah NG, Chrétien M, Gagnon C, Simpson EM. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc Natl Acad Sci U S A. 1997;94(13):6842–6.PubMedPubMedCentralCrossRefGoogle Scholar
  140. McCune JM, Rabin LB, Feinberg MB, Lieberman M, Kosek JC, Reyes GR, Weissman IL. Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. Cell. 1988;53(1):55–67.PubMedCrossRefGoogle Scholar
  141. Meerabux J, Yaspo ML, Roebroek AJ, Van de Ven WJ, Lister TA, Young BD. A new member of the proprotein convertase gene family (LPC) is located at a chromosome translocation breakpoint in lymphomas. Cancer Res. 1996;56(3):448–51.PubMedGoogle Scholar
  142. Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A. 2014;111:15214–9.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Millet JK, Whittaker GR. Host cell proteases: critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120–34.CrossRefPubMedPubMedCentralGoogle Scholar
  144. Misumi Y, Ohkubo K, Sohda M, Takami N, Oda K, Ikehara Y. Intracellular processing of complement pro-C3 and proalbumin is inhibited by rat alpha 1-protease inhibitor variant (Met352----Arg) in transfected cells. Biochem Biophys Res Commun. 1990;171(1):236–42.PubMedCrossRefGoogle Scholar
  145. Misumi Y, Sohda M, Ikehara Y. Sequence of the cDNA encoding rat furin, a possible propeptide-processing endoprotease. Nucleic Acids Res. 1990;18(22):6719.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Mizuno K, Nakamura T, Matsuo H. A unique membrane-bound, calcium-dependent endopeptidase with specificity toward paired basic residues in rat liver Golgi fractions. Biochem Biophys Res Commun. 1989;164(2):780–7.PubMedCrossRefGoogle Scholar
  147. Moehring JM, Inocencio NM, Robertson BJ, Moehring TJ. Expression of mouse furin in a Chinese hamster cell resistant to Pseudomonas exotoxin A and viruses complements the genetic lesion. J Biol Chem. 1993;268(4):2590–4.PubMedPubMedCentralGoogle Scholar
  148. Molloy SS, Bresnahan PA, Leppla SH, Klimpel KR, Thomas G. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. J Biol Chem. 1992;267(23):16396–402.PubMedGoogle Scholar
  149. Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 1999;9(1):28–35. Review.PubMedCrossRefGoogle Scholar
  150. Mori K, Imamaki A, Nagata K, Yonetomi Y, Kiyokage-Yoshimoto R, Martin TJ, Gillespie MT, Nagahama M, Tsuji A, Matsuda Y. Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells. J Biochem. 1999;125(3):627–33.PubMedCrossRefGoogle Scholar
  151. Morikawa Y, Barsov E, Jones I. Legitimate and illegitimate cleavage of human immunodeficiency virus glycoproteins by furin. J Virol. 1993;67(6):3601–4.PubMedPubMedCentralGoogle Scholar
  152. Munzer JS, Basak A, Zhong M, Mamarbachi A, Hamelin J, Savaria D, Lazure C, Hendy GN, Benjannet S, Chrétien M, Seidah NG. In vitro characterization of the novel proprotein convertase PC7. J Biol Chem. 1997;272(32):19672–81.PubMedCrossRefGoogle Scholar
  153. Nagai Y. Virus activation by host proteinases. A pivotal role in the spread of infection, tissue tropism and pathogenicity. Microbiol Immunol. 1995;39(1):1–9. Review.PubMedCrossRefGoogle Scholar
  154. Nakagawa T, Hosaka M, Torii S, Watanabe T, Murakami K, Nakayama K. Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4. J Biochem. 1993;113(2):132–5.PubMedCrossRefGoogle Scholar
  155. Nakagawa T, Suzuki-Nakagawa C, Watanabe A, Asami E, Matsumoto M, Nakano M, Ebihara A, Uddin MN, Suzuki F. Site-1 protease is required for the generation of soluble (pro)renin receptor. J Biochem. 2017;161(4):369–79.PubMedCrossRefGoogle Scholar
  156. Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J. 1997;327(Pt 3):625–35.PubMedPubMedCentralCrossRefGoogle Scholar
  157. Nakayama K, Kim WS, Torii S, Hosaka M, Nakagawa T, Ikemizu J, Baba T, Murakami K. Identification of the fourth member of the mammalian endoprotease family homologous to the yeast Kex2 protease. Its testis-specific expression. J Biol Chem. 1992;267(9):5897–900.PubMedPubMedCentralGoogle Scholar
  158. Neumann G, Horimoto T, Kawaoka Y. Reverse genetics of influenza viruses–applications in research and vaccine design. In: Klenk H-D, Matrosovich MN, Stech J, editors. Avian Influenza. Monogr Virol, vol. 27. Basel: Karger; 2008. p. 118–33.CrossRefGoogle Scholar
  159. Nour N, Basak A, Chrétien M, Seidah NG. Structure-function analysis of the prosegment of the proprotein convertase PC5A. J Biol Chem. 2003;278(5):2886–95.PubMedCrossRefGoogle Scholar
  160. Nour N, Mayer G, Mort JS, Salvas A, Mbikay M, Morrison CJ, Overall CM, Seidah NG. The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases. Mol Biol Cell. 2005;16(11):5215–26.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Oda K, Misumi Y, Ikehara Y, Brennan SO, Hatsuzawa K, Nakayama K. Proteolytic cleavages of proalbumin and complement Pro-C3 in vitro by a truncated soluble form of furin, a mammalian homologue of the yeast Kex2 protease. Biochem Biophys Res Commun. 1992;189(3):1353–61.PubMedCrossRefGoogle Scholar
  162. Ohnishi Y, Shioda T, Nakayama K, Iwata S, Gotoh B, Hamaguchi M, Nagai Y. A furin-defective cell line is able to process correctly the gp160 of human immunodeficiency virus type 1. J Virol. 1994;68(6):4075–9.PubMedPubMedCentralGoogle Scholar
  163. Oliver SL, Sommer M, Zerboni L, Rajamani J, Grose C, Arvin AM. Mutagenesis of varicella-zoster virus glycoprotein B: putative fusion loop residues are essential for viral replication, and the furin cleavage motif contributes to pathogenesis in skin tissue in vivo. J Virol. 2009;83(15):7495–506.PubMedPubMedCentralCrossRefGoogle Scholar
  164. Olmstead AD, Knecht W, Lazarov I, Dixit SB, Jean F. Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents. PLoS Pathog. 2012;8(1):e1002468.PubMedPubMedCentralCrossRefGoogle Scholar
  165. Orlich M, Linder D, Rott R. Trypsin-resistant protease activation mutants of an influenza virus. J Gen Virol. 1995;76(Pt 3):625–33.PubMedCrossRefGoogle Scholar
  166. Ortmann D, Ohuchi M, Angliker H, Shaw E, Garten W, Klenk HD. Proteolytic cleavage of wild type and mutants of the F protein of human parainfluenza virus type 3 by two subtilisin-like endoproteases, furin and Kex2. J Virol. 1994;68(4):2772–6.PubMedPubMedCentralGoogle Scholar
  167. Ozden S, Lucas-Hourani M, Ceccaldi PE, Basak A, Valentine M, Benjannet S, Hamelin J, Jacob Y, Mamchaoui K, Mouly V, Desprès P, Gessain A, Butler-Browne G, Chrétien M, Tangy F, Vidalain PO, Seidah NG. Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: impairment of the maturation of the E2 surface glycoprotein. J Biol Chem. 2008;283(32):21899–908.PubMedCrossRefGoogle Scholar
  168. Pan H, Che FY, Peng B, Steiner DF, Pintar JE, Fricker LD. The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J Neurochem. 2006;98(6):1763–77.PubMedCrossRefGoogle Scholar
  169. Pang YJ, Tan XJ, Li DM, Zheng ZH, Lei RX, Peng XM. Therapeutic potential of furin inhibitors for the chronic infection of hepatitis B virus. Liver Int. 2013;33(8):1230–8.PubMedCrossRefGoogle Scholar
  170. Paquet L, Bergeron F, Boudreault A, Seidah NG, Chrétien M, Mbikay M, Lazure C. The neuroendocrine precursor 7B2 is a sulfated protein proteolytically processed by a ubiquitous furin-like convertase. J Biol Chem. 1994;269(30):19279–85.PubMedGoogle Scholar
  171. Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature. 1995;375(6528):244–7.PubMedCrossRefGoogle Scholar
  172. Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 2007;15(5):545–52.PubMedCrossRefGoogle Scholar
  173. Plaimauer B, Mohr G, Wernhart W, Himmelspach M, Dorner F, Schlokat U. ‘Shed’ furin: mapping of the cleavage determinants and identification of its C-terminus. Biochem J. 2001;354(Pt 3):689–95.PubMedPubMedCentralCrossRefGoogle Scholar
  174. Porter AG, Barber C, Carey NH, Hallewell RA, Threlfall G, Emtage JS. Complete nucleotide sequence of an influenza virus haemagglutinin gene from cloned DNA. Nature. 1979;282(5738):471–7.PubMedCrossRefGoogle Scholar
  175. Pritzer E, Kuroda K, Garten W, Nagai Y, Klenk HD. A host range mutant of Newcastle disease virus with an altered cleavage site for proteolytic activation of the F protein. Virus Res. 1990;15(3):237–42.PubMedCrossRefGoogle Scholar
  176. Puente XS, Sánchez LM, Overall CM, López-Otín C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet. 2003;4(7):544–58. Review.PubMedCrossRefGoogle Scholar
  177. Puthavathana P, Auewarakul P, Charoenying PC, Sangsiriwut K, Pooruk P, Boonnak K, Khanyok R, Thawachsupa P, Kijphati R, Sawanpanyalert P. Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand. J Gen Virol. 2005;86(Pt 2):423–33.PubMedCrossRefGoogle Scholar
  178. Qiu Q, Basak A, Mbikay M, Tsang BK, Gruslin A. Role of pro-IGF-II processing by proprotein convertase 4 in human placental development. Proc Natl Acad Sci U S A. 2005;102(31):11047–52.PubMedPubMedCentralCrossRefGoogle Scholar
  179. Ramos-Molina B, Lindberg I. Phosphorylation and alternative splicing of 7B2 reduce Prohormone Convertase 2 activation. Mol Endocrinol. 2015;29(5):756–64.PubMedPubMedCentralCrossRefGoogle Scholar
  180. Rehemtulla A, Barr PJ, Rhodes CJ, Kaufman RJ. PACE4 is a member of the mammalian propeptidase family that has overlapping but not identical substrate specificity to PACE. Biochemistry. 1993;32(43):11586–90.PubMedCrossRefGoogle Scholar
  181. Remacle AG, Shiryaev SA, Oh ES, Cieplak P, Srinivasan A, Wei G, Liddington RC, Ratnikov BI, Parent A, Desjardins R, Day R, Smith JW, Lebl M, Strongin AY. Substrate cleavage analysis of furin and related proprotein convertases. A comparative study. J Biol Chem. 2008;283(30):20897–906.PubMedPubMedCentralCrossRefGoogle Scholar
  182. Rice CM, Lenches EM, Eddy SR, Shin SJ, Sheets RL, Strauss JH. Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science. 1985;229(4715):726–33.PubMedCrossRefGoogle Scholar
  183. Richards RM, Lowy DR, Schiller JT, Day PM. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc Natl Acad Sci U S A. 2006;103:1522–7.PubMedPubMedCentralCrossRefGoogle Scholar
  184. Richardson C, Hull D, Greer P, Hasel K, Berkovich A, Englund G, Bellini W, Rima B, Lazzarini R. The nucleotide sequence of the mRNA encoding the fusion protein of measles virus (Edmonston strain): a comparison of fusion proteins from several different paramyxoviruses. Virology. 1986;155(2):508–23.PubMedCrossRefGoogle Scholar
  185. Richt JA, Fürbringer T, Koch A, Pfeuffer I, Herden C, Bause-Niedrig I, Garten W. Processing of the Borna disease virus glycoprotein gp94 by the subtilisin-like endoprotease furin. J Virol. 1998;72(5):4528–33.PubMedPubMedCentralGoogle Scholar
  186. Robertson BJ, Moehring JM, Moehring TJ. Defective processing of the insulin receptor in an endoprotease-deficient Chinese hamster cell strain is corrected by expression of mouse furin. J Biol Chem. 1993;268(32):24274–7.PubMedGoogle Scholar
  187. Rockwell NC, Krysan DJ, Komiyama T, Fuller RS. Precursor processing by kex2/furin proteases. Chem Rev. 2002;102(12):4525–48.PubMedCrossRefGoogle Scholar
  188. Roebroek AJ, Schalken JA, Bussemakers MJ, van Heerikhuizen H, Onnekink C, Debruyne FM, Bloemers HP, Van de Ven WJ. Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep. 1986;11(2):117–25.PubMedCrossRefGoogle Scholar
  189. Roebroek AJ, Pauli IG, Zhang Y, van de Ven WJ. cDNA sequence of a Drosophila melanogaster gene, Dfur1, encoding a protein structurally related to the subtilisin-like proprotein processing enzyme furin. FEBS Lett. 1991;289(2):133–7.PubMedCrossRefGoogle Scholar
  190. Roebroek AJ, Umans L, Pauli IG, Robertson EJ, van Leuven F, Van de Ven WJ, Constam DB. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development. 1998;125(24):4863–76.PubMedGoogle Scholar
  191. Roebroek AJ, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, Lauwers A, Van de Ven WJ, Hartmann D, Creemers JW. Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem. 2004;279(51):53442–50.PubMedCrossRefGoogle Scholar
  192. Rousselet E, Benjannet S, Hamelin J, Canuel M, Seidah NG. The proprotein convertase PC7: unique zymogen activation and trafficking pathways. J Biol Chem. 2011;286(4):2728–38.PubMedCrossRefGoogle Scholar
  193. Sakaguchi T, Fujii Y, Kiyotani K, Yoshida T. Correlation of proteolytic cleavage of F protein precursors in paramyxoviruses with expression of the fur, PACE4 and PC6 genes in mammalian cells. J Gen Virol. 1994;75(Pt 10):2821–7.PubMedCrossRefGoogle Scholar
  194. Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell. 1998;2(4):505–14.CrossRefPubMedPubMedCentralGoogle Scholar
  195. Sanchez AJ, Vincent MJ, Nichol ST. Characterization of the glycoproteins of Crimean-Congo hemorrhagic fever virus. J Virol. 2002;76:7263–75.PubMedPubMedCentralCrossRefGoogle Scholar
  196. Sanchez AJ, Vincent MJ, Erickson BR, Nichol ST. Crimean-congo hemorrhagic fever virus glycoprotein precursor is cleaved by Furin-like and SKI-1 proteases to generate a novel 38-kilodalton glycoprotein. J Virol. 2006;80(1):514–25.PubMedPubMedCentralCrossRefGoogle Scholar
  197. Sariola M, Saraste J, Kuismanen E. Communication of post-Golgi elements with early endocytic pathway: regulation of endoproteolytic cleavage of Semliki Forest virus p62 precursor. J Cell Sci. 1995;108(Pt 6):2465–75.PubMedPubMedCentralGoogle Scholar
  198. Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett. 1996;393(1):101–4.PubMedCrossRefGoogle Scholar
  199. Scamuffa N, Calvo F, Chrétien M, Seidah NG, Khatib AM. Proprotein convertases: lessons from knockouts. FASEB J. 2006;20(12):1954–63. Review.PubMedCrossRefGoogle Scholar
  200. Schäfer W, Stroh A, Berghöfer S, Seiler J, Vey M, Kruse ML, Kern HF, Klenk HD, Garten W. Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin. EMBO J. 1995;14(11):2424–35.PubMedPubMedCentralCrossRefGoogle Scholar
  201. Scheid A, Choppin PW. Protease activation mutants of sendai virus. Activation of biological properties by specific proteases. Virology. 1976;69(1):265–77.PubMedCrossRefGoogle Scholar
  202. Schlie K, Maisa A, Lennartz F, Ströher U, Garten W, Strecker T. Characterization of Lassa virus glycoprotein oligomerization and influence of cholesterol on virus replication. J Virol. 2010;84(2):983–92.CrossRefPubMedPubMedCentralGoogle Scholar
  203. Schlie K, Strecker T, Garten W. Maturation cleavage within the ectodomain of Lassa virus glycoprotein relies on stabilization by the cytoplasmic tail. FEBS Lett. 2010;584(21):4379–82.CrossRefPubMedPubMedCentralGoogle Scholar
  204. Schlombs K, Wagner T, Scheel J. Site-1 protease is required for cartilage development in zebrafish. Proc Natl Acad Sci U S A. 2003;100(24):14024–9.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Schmidt I, Skinner M, Siddell S. Nucleotide sequence of the gene encoding the surface projection glycoprotein of coronavirus MHV-JHM. J Gen Virol. 1987;68(Pt 1):47–56.PubMedCrossRefGoogle Scholar
  206. Seidah NG. What lies ahead for the proprotein convertases? Ann N Y Acad Sci. 2011;1220:149–61. Review.PubMedCrossRefGoogle Scholar
  207. Seidah NG, Prat A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem. 2002;38:79–94. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  208. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012;11(5):367–83. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  209. Seidah NG, Gaspar L, Mion P, Marcinkiewicz M, Mbikay M, Chrétien M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 1990;9(6):415–24. Erratum in: DNA Cell Biol. 1990;9(10):789.PubMedCrossRefGoogle Scholar
  210. Seidah NG, Day R, Marcinkiewicz M, Benjannet S, Chrétien M. Mammalian neural and endocrine pro-protein and pro-hormone convertases belonging to the subtilisin family of serine proteinases. Enzyme. 1991;45(5-6):271–84. Review.PubMedCrossRefGoogle Scholar
  211. Seidah NG, Day R, Hamelin J, Gaspar A, Collard MW, Chrétien M. Testicular expression of PC4 in the rat: molecular diversity of a novel germ cell-specific Kex2/subtilisin-like proprotein convertase. Mol Endocrinol. 1992;6(10):1559–70.PubMedPubMedCentralGoogle Scholar
  212. Seidah NG, Benjannet S, Pareek S, Chrétien M, Murphy RA. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett. 1996;379(3):247–50.PubMedCrossRefGoogle Scholar
  213. Seidah NG, Mowla SJ, Hamelin J, Mamarbachi AM, Benjannet S, Touré BB, Basak A, Munzer JS, Marcinkiewicz J, Zhong M, Barale JC, Lazure C, Murphy RA, Chrétien M, Marcinkiewicz M. Mammalian subtilisin/kexin isozyme SKI-1: a widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci U S A. 1999;96(4):1321–6.PubMedPubMedCentralCrossRefGoogle Scholar
  214. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100(3):928–33.PubMedPubMedCentralCrossRefGoogle Scholar
  215. Seidah NG, Mayer G, Zaid A, Rousselet E, Nassoury N, Poirier S, Essalmani R, Prat A. The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol. 2008;40(6-7):1111–25. Review.PubMedCrossRefGoogle Scholar
  216. Seidah NG, Sadr MS, Chrétien M, Mbikay M. The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J Biol Chem. 2013;288(30):21473–81.PubMedPubMedCentralCrossRefGoogle Scholar
  217. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114(6):1022–36. Review.PubMedCrossRefGoogle Scholar
  218. Shinde U, Thomas G. Insights from bacterial subtilases into the mechanisms of intramolecular chaperone-mediated activation of furin. Methods Mol Biol. 2011;768:59–106. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  219. Shiryaev SA, Chernov AV, Golubkov VS, Thomsen E, Chudin E, Chee M, Kozlov I, Strongin AY, Cieplak P. High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome. PLoS One. 2013;8:e54290.PubMedPubMedCentralCrossRefGoogle Scholar
  220. Siezen RJ, Creemers JW, Van de Ven WJ. Homology modelling of the catalytic domain of human furin. A model for the eukaryotic subtilisin-like proprotein convertases. Eur J Biochem. 1994;222(2):255–66.PubMedCrossRefGoogle Scholar
  221. Smeekens SP, Steiner DF. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J Biol Chem. 1990;265(6):2997–3000.PubMedPubMedCentralGoogle Scholar
  222. Smeekens SP, Avruch AS, LaMendola J, Chan SJ, Steiner DF. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc Natl Acad Sci U S A. 1991;88(2):340–4.PubMedPubMedCentralCrossRefGoogle Scholar
  223. Sorem J, Longnecker R. Cleavage of Epstein-Barr virus glycoprotein B is required for full function in cell-cell fusion with both epithelial and B cells. J Gen Virol. 2009;90(Pt 3):591–5.PubMedPubMedCentralCrossRefGoogle Scholar
  224. Spiesschaert B, Stephanowitz H, Krause E, Osterrieder N, Azab W. Glycoprotein B of equine herpesvirus type 1 has two recognition sites for subtilisin-like proteases that are cleaved by furin. J Gen Virol. 2016;97(5):1218–28.PubMedCrossRefGoogle Scholar
  225. Stadler K, Allison SL, Schalich J, Heinz FX. Proteolytic activation of tick-borne encephalitis virus by furin. J Virol. 1997;71:8475–81.PubMedPubMedCentralGoogle Scholar
  226. Stawowy P, Kallisch H, Borges Pereira Stawowy N, Stibenz D, Veinot JP, Gräfe M, Seidah NG, Chrétien M, Fleck E, Graf K. Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis. Virchows Arch. 2005;446(4):351–9.PubMedCrossRefGoogle Scholar
  227. Stech J, Garn H, Wegmann M, Wagner R, Klenk HD. A new approach to an influenza live vaccine: modification of the cleavage site of hemagglutinin. Nat Med. 2005;11(6):683–9.PubMedCrossRefGoogle Scholar
  228. Steiner DF. The proprotein convertases. Curr Opin Chem Biol. 1998;2:31–9.PubMedCrossRefGoogle Scholar
  229. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science. 1967;157(3789):697–700.PubMedCrossRefGoogle Scholar
  230. Stieneke-Gröber A, Vey M, Angliker H, Shaw E, Thomas G, Roberts C, Klenk HD, Garten W. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J. 1992;11(7):2407–14.PubMedPubMedCentralCrossRefGoogle Scholar
  231. Strauss EG, Rice CM, Strauss JH. Complete nucleotide sequence of the genomic RNA of Sindbis virus. Virology. 1984;133(1):92–110.PubMedCrossRefGoogle Scholar
  232. Stroh A, Schäfer W, Berghöfer S, Eickmann M, Teuchert M, Bürger I, Klenk HD, Garten W. A mono phenylalanine-based motif (F790) and a leucine-dependent motif (LI760) mediate internalization of furin. Eur J Cell Biol. 1999;78(3):151–60.PubMedCrossRefGoogle Scholar
  233. Sturman LS, Holmes KV. Proteolytic cleavage of peplomeric glycoprotein E2 of MHV yields two 90K subunits and activates cell fusion. Adv Exp Med Biol. 1984;173:25–35.PubMedCrossRefGoogle Scholar
  234. Sucic JF, Moehring JM, Inocencio NM, Luchini JW, Moehring TJ. Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain. Biochem J. 1999;339(Pt 3):639–47.PubMedPubMedCentralCrossRefGoogle Scholar
  235. Takahashi S, Nakagawa T, Banno T, Watanabe T, Murakami K, Nakayama K. Localization of furin to the trans-Golgi network and recycling from the cell surface involves Ser and Tyr residues within the cytoplasmic domain. J Biol Chem. 1995;270(47):28397–401.PubMedCrossRefGoogle Scholar
  236. Tangrea MA, Bryan PN, Sari N, Orban J. Solution structure of the pro-hormone convertase 1 pro-domain from Mus musculus. J Mol Biol. 2002;320(4):801–12.PubMedCrossRefGoogle Scholar
  237. Taylor NA, Van De Ven WJ, Creemers JW. Curbing activation: proprotein convertases in homeostasis and pathology. FASEB J. 2003;17(10):1215–27. Review.PubMedCrossRefGoogle Scholar
  238. Teuchert M, Schäfer W, Berghöfer S, Hoflack B, Klenk HD, Garten W. Sorting of furin at the trans-Golgi network. Interaction of the cytoplasmic tail sorting signals with AP-1 Golgi-specific assembly proteins. J Biol Chem. 1999;274(12):8199–207.PubMedCrossRefGoogle Scholar
  239. Teuchert M, Berghöfer S, Klenk HD, Garten W. Recycling of furin from the plasma membrane. Functional importance of the cytoplasmic tail sorting signals and interaction with the AP-2 adaptor medium chain subunit. J Biol Chem. 1999;274(51):36781–9.PubMedCrossRefGoogle Scholar
  240. Than ME, Henrich S, Bourenkov GP, Bartunik HD, Huber R, Bode W. The endoproteinase furin contains two essential Ca2+ ions stabilizing its N-terminus and the unique S1 specificity pocket. Acta Crystallogr D Biol Crystallogr. 2005;61(Pt 5):505–12.PubMedCrossRefGoogle Scholar
  241. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002;3(10):753–66. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  242. Thomas G, Thorne BA, Thomas L, Allen RG, Hruby DE, Fuller R, Thorner J. Yeast KEX2 endopeptidase correctly cleaves a neuroendocrine prohormone in mammalian cells. Science. 1988;241(4862):226–30.PubMedCrossRefGoogle Scholar
  243. Toyoda T, Sakaguchi T, Imai K, Inocencio NM, Gotoh B, Hamaguchi M, Nagai Y. Structural comparison of the cleavage-activation site of the fusion glycoprotein between virulent and avirulent strains of Newcastle disease virus. Virology. 1987;158(1):242–7.PubMedPubMedCentralCrossRefGoogle Scholar
  244. Tsuji A, Sakurai K, Kiyokage E, Yamazaki T, Koide S, Toida K, Ishimura K, Matsuda Y. Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix. Biochim Biophys Acta. 2003;1645(1):95–104.PubMedCrossRefGoogle Scholar
  245. Tsuneoka M, Nakayama K, Hatsuzawa K, Komada M, Kitamura N, Mekada E. Evidence for involvement of furin in cleavage and activation of diphtheria toxin. J Biol Chem. 1993;268(35):26461–5.PubMedPubMedCentralGoogle Scholar
  246. Turpeinen H, Oksanen A, Kivinen V, Kukkurainen S, Uusimäki A, Rämet M, Parikka M, Hytönen VP, Nykter M, Pesu M. Proprotein convertase subtilisin/kexin type 7 (PCSK7) is essential for the zebrafish development and bioavailability of transforming growth factor β1a (TGFβ1a). J Biol Chem. 2013;288(51):36610–23.  https://doi.org/10.1074/jbc.M113.453183.CrossRefPubMedPubMedCentralGoogle Scholar
  247. van de Loo JW, Teuchert M, Pauli I, Plets E, Van de Ven WJ, Creemers JW. Dynamic palmitoylation of lymphoma proprotein convertase prolongs its half-life, but is not essential for trans-Golgi network localization. Biochem J. 2000;352(Pt 3):827–33.PubMedPubMedCentralGoogle Scholar
  248. van de Ven WJ, Voorberg J, Fontijn R, Pannekoek H, van den Ouweland AM, van Duijnhoven HL, Roebroek AJ, Siezen RJ. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep. 1990;14(4):265–75.PubMedCrossRefGoogle Scholar
  249. Vey M, Orlich M, Adler S, Klenk HD, Rott R, Garten W. Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R. Virology. 1992;188(1):408–13.PubMedCrossRefGoogle Scholar
  250. Vey M, Schäfer W, Berghöfer S, Klenk HD, Garten W. Maturation of the trans-Golgi network protease furin: compartmentalization of propeptide removal, substrate cleavage, and COOH-terminal truncation. J Cell Biol. 1994;127(6 Pt 2):1829–42.PubMedCrossRefGoogle Scholar
  251. Vey M, Schäfer W, Reis B, Ohuchi R, Britt W, Garten W, Klenk HD, Radsak K. Proteolytic processing of human cytomegalovirus glycoprotein B (gpUL55) is mediated by the human endoprotease furin. Virology. 1995;206(1):746–9.PubMedCrossRefGoogle Scholar
  252. Vincent MJ, Sanchez AJ, Erickson BR, Basak A, Chretien M, Seidah NG, Nichol ST. Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1. J Virol. 2003;77(16):8640–9.PubMedPubMedCentralCrossRefGoogle Scholar
  253. Volchkov VE, Feldmann H, Volchkova VA, Klenk HD. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci U S A. 1998;95(10):5762–7.PubMedPubMedCentralCrossRefGoogle Scholar
  254. Volchkov VE, Volchkova VA, Ströher U, Becker S, Dolnik O, Cieplik M, Garten W, Klenk HD, Feldmann H. Proteolytic processing of Marburg virus glycoprotein. Virology. 2000;268(1):1–6.PubMedCrossRefGoogle Scholar
  255. Volchkova VA, Klenk HD, Volchkov VE. Delta-peptide is the carboxy-terminal cleavage fragment of the nonstructural small glycoprotein sGP of Ebola virus. Virology. 1999;265(1):164–71.PubMedCrossRefGoogle Scholar
  256. Voorhees P, Deignan E, van Donselaar E, Humphrey J, Marks MS, Peters PJ, Bonifacino JS. An acidic sequence within the cytoplasmic domain of furin functions as a determinant of trans-Golgi network localization and internalization from the cell surface. EMBO J. 1995;14(20):4961–75.PubMedPubMedCentralCrossRefGoogle Scholar
  257. Walker JA, Kawaoka Y. Importance of conserved amino acids at the cleavage site of the haemagglutinin of a virulent avian influenza A virus. J Gen Virol. 1993;74(Pt 2):311–4.PubMedCrossRefGoogle Scholar
  258. Walker JA, Molloy SS, Thomas G, Sakaguchi T, Yoshida T, Chambers TM, Kawaoka Y. Sequence specificity of furin, a proprotein-processing endoprotease, for the hemagglutinin of a virulent avian influenza virus. J Virol. 1994;68(2):1213–8.PubMedPubMedCentralGoogle Scholar
  259. Wang M, Shen S, Wang H, Hu Z, Becnel J, Vlak JM. Deltabaculoviruses encode a functional type I budded virus envelope fusion protein. J Gen Virol. 2017;98(4):847–52.PubMedCrossRefGoogle Scholar
  260. Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Govorkova EA, McClain-Moss LR, Peiris JS, Rehg JE, Tuomanen EI, Webster RG. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet. 2004;363(9415):1099–103.PubMedCrossRefGoogle Scholar
  261. Weider E, Susan-Resiga D, Essalmani R, Hamelin J, Asselin MC, Nimesh S, Ashraf Y, Wycoff KL, Zhang J, Prat A, Seidah NG. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) single domain antibodies are potent inhibitors of low density lipoprotein receptor degradation. J Biol Chem. 2016;291(32):16659–71.PubMedPubMedCentralCrossRefGoogle Scholar
  262. White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic. 2016;17(6):593–614.PubMedPubMedCentralCrossRefGoogle Scholar
  263. Williamson DM, Elferich J, Ramakrishnan P, Thomas G, Shinde U. The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin. J Biol Chem. 2013;288(26):19154–65. <prodomain, His69 function as a pH-sensor>.PubMedPubMedCentralCrossRefGoogle Scholar
  264. Wise RJ, Barr PJ, Wong PA, Kiefer MC, Brake AJ, Kaufman RJ. Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. Proc Natl Acad Sci U S A. 1990;87(23):9378–82.PubMedPubMedCentralCrossRefGoogle Scholar
  265. Wong E, Maretzky T, Peleg Y, Blobel CP, Sagi I. The functional maturation of A Disintegrin and Metalloproteinase (ADAM) 9, 10, and 17 requires processing at a newly identified Proprotein Convertase (PC) cleavage site. J Biol Chem. 2015;290(19):12135–46.PubMedPubMedCentralCrossRefGoogle Scholar
  266. Wouters S, Leruth M, Decroly E, Vandenbranden M, Creemers JW, van de Loo JW, Ruysschaert JM, Courtoy PJ. Furin and proprotein convertase 7 (PC7)/lymphoma PC endogenously expressed in rat liver can be resolved into distinct post-Golgi compartments. Biochem J. 1998;336:311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  267. Xiao Y, Chen G, Richard J, Rougeau N, Li H, Seidah NG, Cohen EA. Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases. Virology. 2008;372:384–97.PubMedCrossRefGoogle Scholar
  268. Yamshchikov GV, Ritter GD, Vey M, Compans RW. Assembly of SIV virus-like particles containing envelope proteins using a baculovirus expression system. Virology. 1995;214(1):50–8.PubMedCrossRefGoogle Scholar
  269. Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci U S A. 2001;98(24):13607–12.PubMedPubMedCentralCrossRefGoogle Scholar
  270. Yang HY, Zheng NQ, Li DM, Gu L, Peng XM. Entecavir combined with furin inhibitor simultaneously reduces hepatitis B virus replication and e antigen secretion. Virol J. 2014;11:165.PubMedPubMedCentralCrossRefGoogle Scholar
  271. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6:1355–64.CrossRefPubMedPubMedCentralGoogle Scholar
  272. Zhang X, Fugère M, Day R, Kielian M. Furin processing and proteolytic activation of Semliki Forest virus. J Virol. 2003;77(5):2981–9.PubMedPubMedCentralCrossRefGoogle Scholar
  273. Zhou A, Martin S, Lipkind G, LaMendola J, Steiner DF. Regulatory roles of the P domain of the subtilisin-like prohormone convertases. J Biol Chem. 1998;273(18):11107–14.PubMedCrossRefGoogle Scholar
  274. Zhu X, Lindberg I. 7B2 facilitates the maturation of proPC2 in neuroendocrine cells and is required for the expression of enzymatic activity. J Cell Biol. 1995;129(6):1641–50.PubMedCrossRefGoogle Scholar
  275. Zimmer G, Budz L, Herrler G. Proteolytic activation of respiratory syncytial virus fusion protein. Cleavage at two furin consensus sequences. J Biol Chem. 2001;276(34):31642–50.PubMedCrossRefGoogle Scholar
  276. Zimmer G, Rohn M, McGregor GP, Schemann M, Conzelmann KK, Herrler G. Virokinin, a bioactive peptide of the tachykinin family, is released from the fusion protein of bovine respiratory syncytial virus. J Biol Chem. 2003;278(47):46854–61.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of VirologyPhilipps-University MarburgMarburgGermany

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