Amebiasis pp 279-304 | Cite as

Molecular Basis of the Trafficking of Cysteine Proteases and Other Soluble Lysosomal Proteins in Entamoeba histolytica

  • Kumiko Nakada-Tsukui
  • Tomoyoshi Nozaki


Cysteine proteases (CPs) are the essential virulent factor of Entamoeba histolytica. Although the physiological and pathological roles of CPs have been demonstrated, the molecular basis of intracellular trafficking of CPs has only begun to be unveiled. Recent work has revealed the mechanisms of intra- and extracellular transport of CPs and other soluble lysosomal proteins in E. histolytica. Such proteins involved in the mechanisms include Rab small GTPases, their effectors, the intrinsic inhibitor of CPs, and a unique family of receptors responsible for lysosomal transport. In this chapter, we give an overview of the current understanding of molecules and mechanisms involved in the transport of CPs and other soluble lysosomal proteins in E. histolytica.


Entamoeba Histolytica Carbohydrate Recognition Domain Lysosomal Protein Lysozyme Gene Histolytica Trophozoite 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Courtney Spears and Andrew J. Roger, Centre for Comparative Genomics and Evolutionary Bioinformatics, Department of Biochemistry and Molecular Biology at Dalhousie University for the information on Mastigamoeba genome information, and Konomi Marumo for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to T.N. (23117001, 23117005, 23390099) and K.N.-T. (24590513), a Grant-in-Aid on Bilateral Programs of Joint Research Projects and Seminars from Japan Society for the Promotion of Science, a Grant-in-Aid on Strategic International Research Cooperative Program from Japan Science and Technology Agency, a grant for research on emerging and re-emerging infectious diseases from the Ministry of Health, Labour and Welfare of Japan (H23-Shinko-ippan-014) to T.N., a grant for research to promote the development of anti-AIDS pharmaceuticals from the Japan Health Sciences Foundation (KHA1101) to T.N., Strategic International Research Cooperative Program from Japan Science and Technology Agency to T.N., and by Global COE Program (Global COE for Human Metabolomic Systems Biology) from MEXT, Japan to T.N


  1. 1.
    Que X, Reed SL (2000) Cysteine proteinases and the pathogenesis of amebiasis. Clin Microbiol Rev 13:196–206PubMedCentralPubMedGoogle Scholar
  2. 2.
    Hellberg A, Nickel R, Lotter H, Tannich E, Bruchhaus I (2001) Overexpression of cysteine proteinase 2 in Entamoeba histolytica or Entamoeba dispar increases amoeba-induced monolayer destruction in vitro but does not augment amoebic liver abscess formation in gerbils. Cell Microbiol 3:13–20PubMedGoogle Scholar
  3. 3.
    Ackers JP, Mirelman D (2006) Progress in research on Entamoeba histolytica pathogenesis. Curr Opin Microbiol 9:367–373PubMedGoogle Scholar
  4. 4.
    Ralston KS, Petri WA Jr (2011) Tissue destruction and invasion by Entamoeba histolytica. Trends Parasitol 27:254–263PubMedCentralPubMedGoogle Scholar
  5. 5.
    Brinen LS, Que X, McKerrow JH, Reed SL (2000) Homology modeling of Entamoeba histolytica cysteine proteinases reveals the basis for cathepsin L-like structure with cathepsin B-like specificity. Arch Med Res 31:S63–S64PubMedGoogle Scholar
  6. 6.
    Hellberg A, Nowak N, Leippe M, Tannich E, Bruchhaus I (2002) Recombinant expression and purification of an enzymatically active cysteine proteinase of the protozoan parasite Entamoeba histolytica. Protein Expr Purif 24:131–137PubMedGoogle Scholar
  7. 7.
    Bruchhaus I, Loftus BJ, Hall N, Tannich E (2003) The intestinal protozoan parasite Entamoeba histolytica contains 20 cysteine protease genes, of which only a small subset is expressed during in vitro cultivation. Eukaryot Cell 2:501–509PubMedCentralPubMedGoogle Scholar
  8. 8.
    Que X, Kim SH, Sajid M, Eckmann L, Dinarello CA, McKerrow JH, Reed SL (2003) A surface amebic cysteine proteinase inactivates interleukin-18. Infect Immun 71:1274–1280PubMedCentralPubMedGoogle Scholar
  9. 9.
    Gilchrist CA, Houpt E, Trapaidze N, Fei Z, Crasta O, Asgharpour A, Evans C, Martino-Catt S, Baba DJ, Stroup S, Hamano S, Ehrenkaufer G, Okada M, Singh U, Nozaki T, Mann BJ, Petri WA Jr (2006) Impact of intestinal colonization and invasion on the Entamoeba histolytica transcriptome. Mol Biochem Parasitol 147:163–176PubMedGoogle Scholar
  10. 10.
    MacFarlane RC, Singh U (2006) Identification of differentially expressed genes in virulent and nonvirulent Entamoeba species: potential implications for amebic pathogenesis. Infect Immun 74:340–351PubMedCentralPubMedGoogle Scholar
  11. 11.
    Meléndez-López SG, Herdman S, Hirata K, Choi MH, Choe Y, Craik C, Caffrey CR, Hansell E, Chávez-Munguía B, Chen YT, Roush WR, McKerrow J, Eckmann L, Guo J, Stanley SL Jr, Reed SL (2007) Use of recombinant Entamoeba histolytica cysteine proteinase 1 to identify a potent inhibitor of amebic invasion in a human colonic model. Eukaryot Cell 6:1130–1136PubMedCentralPubMedGoogle Scholar
  12. 12.
    He C, Nora GP, Schneider EL, Kerr ID, Hansell E, Hirata K, Gonzalez D, Sajid M, Boyd SE, Hruz P, Cobo ER, Le C, Liu WT, Eckmann L, Dorrestein PC, Houpt ER, Brinen LS, Craik CS, Roush WR, McKerrow J, Reed SL (2010) A novel Entamoeba histolytica cysteine proteinase, EhCP4, is key for invasive amebiasis and a therapeutic target. J Biol Chem 285:18516–18527PubMedCentralPubMedGoogle Scholar
  13. 13.
    Hamann L, Nickel R, Tannich E (1995) Transfection and continuous expression of heterologous genes in the protozoan parasite Entamoeba histolytica. Proc Natl Acad Sci USA 92:8975–8979PubMedCentralPubMedGoogle Scholar
  14. 14.
    Vines RR, Purdy JE, Ragland BD, Samuelson J, Mann BJ, Petri WA Jr (1995) Stable episomal transfection of Entamoeba histolytica. Mol Biochem Parasitol 71:265–267PubMedGoogle Scholar
  15. 15.
    Hamann L, Buss H, Tannich E (1997) Tetracycline-controlled gene expression in Entamoeba histolytica. Mol Biochem Parasitol 84:83–91PubMedGoogle Scholar
  16. 16.
    Ramakrishnan G, Vines RR, Mann BJ, Petri WA Jr (1997) A tetracycline-inducible gene expression system in Entamoeba histolytica. Mol Biochem Parasitol 84:93–100PubMedGoogle Scholar
  17. 17.
    Nakada-Tsukui K, Tsuboi K, Furukawa A, Yamada Y, Nozaki T (2012) A novel class of cysteine protease receptors that mediate lysosomal transport. Cell Microbiol 14:1299–1317PubMedCentralPubMedGoogle Scholar
  18. 18.
    Marion S, Laurent C, Guillén N (2005) Signalization and cytoskeleton activity through myosin IB during the early steps of phagocytosis in Entamoeba histolytica: a proteomic approach. Cell Microbiol 7:1504–1518PubMedGoogle Scholar
  19. 19.
    Mitra BN, Yasuda T, Kobayashi S, Saito-Nakano Y, Nozaki T (2005) Differences in morphology of phagosomes and kinetics of acidification and degradation in phagosomes between the pathogenic Entamoeba histolytica and the non-pathogenic Entamoeba dispar. Cell Motil Cytoskeleton 62:84–99PubMedGoogle Scholar
  20. 20.
    Okada M, Huston CD, Mann BJ, Petri WA Jr, Kita K, Nozaki T (2005) Proteomic analysis of phagocytosis in the enteric protozoan parasite Entamoeba histolytica. Eukaryot Cell 4:827–831PubMedCentralPubMedGoogle Scholar
  21. 21.
    Okada M, Huston CD, Oue M, Mann BJ, Petri WA Jr, Kita K, Nozaki T (2006) Kinetics and strain variation of phagosome proteins of Entamoeba histolytica by proteomic analysis. Mol Biochem Parasitol 145:171–183PubMedGoogle Scholar
  22. 22.
    Teixeira JE, Huston CD (2008) Evidence of a continuous endoplasmic reticulum in the protozoan parasite Entamoeba histolytica. Eukaryot Cell 7:1222–1226PubMedCentralPubMedGoogle Scholar
  23. 23.
    Vaithilingam A, Teira JE, Huston CD (2008) Endoplasmic reticulum continuity in the protozoan parasite Entamoeba histolytica. Commun Integr Biol 1:172–174PubMedCentralPubMedGoogle Scholar
  24. 24.
    Leippe M (1997) Amoebapores. Parasitol Today 13:178–183PubMedGoogle Scholar
  25. 25.
    Bracha R, Nuchamowitz Y, Leippe M, Mirelman D (1999) Antisense inhibition of amoebapore expression in Entamoeba histolytica causes a decrease in amoebic virulence. Mol Microbiol 34:463–472PubMedGoogle Scholar
  26. 26.
    Bracha R, Nuchamowitz Y, Mirelman D (2003) Transcriptional silencing of an amoebapore gene in Entamoeba histolytica: molecular analysis and effect on pathogenicity. Eukaryot Cell 2:295–305PubMedCentralPubMedGoogle Scholar
  27. 27.
    Leroy A, Mareel M, De Bruyne G, Bailey G, Nelis H (1995) Metastasis of Entamoeba histolytica compared to colon cancer: one more step in invasion. Invasion Metastasis 14:177–191Google Scholar
  28. 28.
    Bernacki RJ, Niedbala MJ, Korytnyk W (1985) Glycosidases in cancer and invasion. Cancer Metastasis Rev 4:81–101PubMedGoogle Scholar
  29. 29.
    Liotta LA (1984) Tumor invasion and metastases: role of the basement membrane. Am J Pathol 117:339–348PubMedCentralPubMedGoogle Scholar
  30. 30.
    Huldt G, Davies P, Allison AC, Schorlemmer HU (1979) Interactions between Entamoeba histolytica and complement. Nature (Lond) 18:214–216Google Scholar
  31. 31.
    Chipman DM, Grisaro V, Sharon N (1967) The binding of oligosaccharides containing N-acetylglucosamine and N-acetylmuramic acid to lysozyme. J Biol Chem 242:4388–4394PubMedGoogle Scholar
  32. 32.
    Davis PH, Scholze J, Stanley SL Jr (2007) Transcriptomic comparison of two Entamoeba histolytica strains with defined virulence phenotypes identifies new virulence factor candidates and key differences in the expression patterns of cysteine proteases, lectin light chains, and calmodulin. Mol Biochem Parasitol 151:118–128PubMedGoogle Scholar
  33. 33.
    Ali IKM, Ehrenkaufer GM, Hackney JA, Singh U (2008) Growth of the protozoan parasite Entamoeba histolytica in 5-azacytidine has limited effects on parasite gene expression. BMC Genomics 8:7Google Scholar
  34. 34.
    Sehgal D, Bhattacharya A, Bhattacharya S (1996) Pathogenesis of infection by Entamoeba histolytica. J Biosci 21:423–432Google Scholar
  35. 35.
    Temesvari LA, Harris EN, Stanley SL Jr, Cardelli JA (1999) Early and late endosomal compartments of Entamoeba histolytica are enriched in cysteine proteases, acid phosphatase and several Ras-related Rab GTPases. Mol Biochem Parasitol 103:225–241PubMedGoogle Scholar
  36. 36.
    Ghosh P, Dahms NM, Kornfeld S (2003) Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4:202–212PubMedGoogle Scholar
  37. 37.
    Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614PubMedGoogle Scholar
  38. 38.
    Marcusson EG, Horazdovsky BF, Cereghino JL, Gharakhanian E, Emr SD (1994) The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 77:579–586PubMedGoogle Scholar
  39. 39.
    Lefrancois S, Zeng J, Hassan AJ, Canue M, Morales CR (2003) The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J 22:6430–6437PubMedCentralPubMedGoogle Scholar
  40. 40.
    Ni X, Morales CR (2006) The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor. Traffic 7:889–902PubMedGoogle Scholar
  41. 41.
    Canuel M, Lefrancois S, Zeng J, Morales CR (2008) AP-1 and retromer play opposite roles in the trafficking of sortilin between the Golgi apparatus and the lysosomes. Biochem Biophys Res Commun 366:724–730PubMedGoogle Scholar
  42. 42.
    Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81:153–208PubMedGoogle Scholar
  43. 43.
    Novick P, Zerial M (1997) The diversity of Rab proteins in vesicle transport. Curr Opin Cell Biol 9:496–504PubMedGoogle Scholar
  44. 44.
    Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525PubMedGoogle Scholar
  45. 45.
    Mizuno-Yamasaki E, Rivera-Molina F, Novick P (2012) GTPase networks in membrane traffic. Annu Rev Biochem 81:637–659PubMedCentralPubMedGoogle Scholar
  46. 46.
    Saito-Nakano Y, Loftus BJ, Hall N, Nozaki T (2005) The diversity of Rab GTPases in Entamoeba histolytica. Exp Parasitol 110:244–252PubMedGoogle Scholar
  47. 47.
    Nakada-Tsukui K, Saito-Nakano Y, Husain A, Nozaki T (2010) Conservation and function of Rab small GTPases in Entamoeba: annotation of E. invadens Rab and its use for the understanding of Entamoeba biology. Exp Parasitol 126:337–347PubMedGoogle Scholar
  48. 48.
    Barr F, Lambright DG (2010) Rab GEFs and GAPs. Curr Opin Cell Biol 22:461–470PubMedCentralPubMedGoogle Scholar
  49. 49.
    Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93:269–309PubMedGoogle Scholar
  50. 50.
    Magee AI, Newman CM, Giannakouros T, Hancock JF, Fawell E, Armstrong J (1992) Lipid modifications and function of the ras superfamily of proteins. Biochem Soc Trans 20:497–499PubMedGoogle Scholar
  51. 51.
    Glomset JA, Farnsworth CC (1994) Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes. Annu Rev Cell Biol 10:181–205PubMedGoogle Scholar
  52. 52.
    Casey PJ, Seabra MC (1996) Protein prenyltransferases. J Biol Chem 271:5289–5292PubMedGoogle Scholar
  53. 53.
    Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, Janssen H, Wubbolts R, Neefjes J (2001) The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 11:1680–1685PubMedGoogle Scholar
  54. 54.
    Patki V, Virbasius J, Lane WS, Toh BH, Shpetner HS, Corvera S (1997) Identification of an early endosomal protein regulated by phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 94:7326–7330PubMedCentralPubMedGoogle Scholar
  55. 55.
    Wang T, Ming Z, Xiaochun W, Hong W (2011) Rabu7: role of its protein interaction cascades in endo-lysosomal traffic. Cell Signal 23:516–521PubMedGoogle Scholar
  56. 56.
    Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B (2000) Rab7: a key to lysosome biogenesis. Mol Biol Cell 11:467–480PubMedCentralPubMedGoogle Scholar
  57. 57.
    Jäger S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848PubMedGoogle Scholar
  58. 58.
    Jordens I, Westbroek W, Marsman M, Rocha N, Mommaas M, Huizing M, Lambert J, Naeyaert JM, Neefjes J (2006) Rab7 and Rab27a control two motor protein activities involved in melanosomal transport. Pigment Cell Res 19:412–423PubMedGoogle Scholar
  59. 59.
    Kinchen JM, Ravichandran KS (2010) Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature (Lond) 464:778–782Google Scholar
  60. 60.
    Pereira-Leal JB, Seabra MC (2001) Evolution of the Rab family of small GTP-binding proteins. J Mol Biol 313:889–901PubMedGoogle Scholar
  61. 61.
    Quevillon E, Spielmann T, Brahimi K, Chattopadhyay D, Yeramian E, Langsley G (2003) The Plasmodium falciparum family of Rab GTPases. Gene (Amst) 306:13–25Google Scholar
  62. 62.
    Acker JP, Dhir V, Field MC (2005) A bioinformatics analysis of the RAB genes of Trypanosoma brucei. Mol Biochem Parasitol 141:89–97Google Scholar
  63. 63.
    Berriman M, Ghedin E, Hertz-Fowler C, Blandin G, Renauld H, Bartholomeu DC, Lennard NJ, Caler E, Hamlin NE, Haas B, Böhme U, Hannick L, Aslett MA, Shallom J, Marcello L, Hou L, Wickstead B, Alsmark UC, Arrowsmith C, Atkin RJ, Barron AJ, Bringaud F, Brooks K, Carrington M, Cherevach I, Chillingworth TJ, Churcher C, Clark LN, Corton CH, Cronin A, Davies RM, Doggett J, Djikeng A, Feldblyum T, Field MC, Fraser A, Goodhead I, Hance Z, Harper D, Harris BR, Hauser H, Hostetler J, Ivens A, Jagels K, Johnson D, Johnson J, Jones K, Kerhornou AX, Koo H, Larke N, Landfear S, Larkin C, Leech V, Line A, Lord A, Macleod A, Mooney PJ, Moule S, Martin DM, Morgan GW, Mungall K, Norbertczak H, Ormond D, Pai G, Peacock CS, Peterson J, Quail MA, Rabbinowitsch E, Rajandream MA, Reitter C, Salzberg SL, Sanders M, Schobel S, Sharp S, Simmonds M, Simpson AJ, Tallon L, Turner CM, Tait A, Tivey AR, Van Aken S, Walker D, Wanless D, Wang S, White B, White O, Whitehead S, Woodward J, Wortman J, Adams MD, Embley TM, Gull K, Ullu E, Barry JD, Fairlamb AH, Opperdoes F, Barrell BG, Donelson JE, Hall N, Fraser CM, Melville SE, El-Sayed NM (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309:416–422PubMedGoogle Scholar
  64. 64.
    Lal K, Field MC, Carlton JM, Warwicker J, Hirt RP (2005) Identification of a very large Rab GTPase family in the parasitic protozoan Trichomonas vaginalis. Mol Biochem Parasitol 143:226–235PubMedGoogle Scholar
  65. 65.
    Borg S, Brandstrup B, Jensen TJ, Poulsen C (1997) Identification of new protein species among 33 different small GTP-binding proteins encoded by cDNAs from Lotus japonicus, and expression of corresponding mRNAs in developing root nodules. Plant J 11:237–250PubMedGoogle Scholar
  66. 66.
    Mazel A, Leshem Y, Tiwari BS, Levine A (2004) Induction of salt and osmotic stress tolerance by overexpression of an intracellular vesicle trafficking protein AtRab7 (AtRabG3e). Plant Physiol 134:118–128PubMedCentralPubMedGoogle Scholar
  67. 67.
    Saito-Nakano Y, Yasuda T, Nakada-Tsukui K, Leippe M, Nozaki T (2004) Rab5-associated vacuoles play a unique role in phagocytosis of the enteric protozoan parasite Entamoeba histolytica. J Biol Chem 279:49497–49507PubMedGoogle Scholar
  68. 68.
    Nakada-Tsukui K, Saito-Nakano Y, Ali V, Nozaki T (2005) A retromerlike complex is a novel Rab7 effector that is involved in the transport of the virulence factor cysteine protease in the enteric protozoan parasite Entamoeba histolytica. Mol Biol Cell 16:5294–5303PubMedCentralPubMedGoogle Scholar
  69. 69.
    Nozaki T, Nakada-Tsukui K (2006) Membrane trafficking as a virulence mechanism of the enteric protozoan parasite Entamoeba histolytica. Parasitol Res 98:179–183PubMedGoogle Scholar
  70. 70.
    Saito-Nakano Y, Mitra BN, Nakada-Tsukui K, Sato D, Nozaki T (2007) Two Rab7 isotypes, EhRab7A and EhRab7B, play distinct roles in biogenesis of lysosomes and phagosomes in the enteric protozoan parasite Entamoeba histolytica. Cell Microbiol 9:1796–1808PubMedGoogle Scholar
  71. 71.
    Ullrich O, Reinsch S, Urbe S, Zerial M, Parton RG (1996) Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol 135:913–924PubMedGoogle Scholar
  72. 72.
    Chen W, Feng Y, Chen D, Wandinger-Ness A (1998) Rab11 is required for trans-golgi network-to-plasma membrane transport and a preferential target for GDP dissociation inhibitor. Mol Biol Cell 9:3241–3257PubMedCentralPubMedGoogle Scholar
  73. 73.
    Casanova JE, Wang X, Kumar R, Bhartur SG, Navarre J et al (1999) Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol Biol Cell 10:47–61PubMedCentralPubMedGoogle Scholar
  74. 74.
    Wang X, Kumar R, Navarre J, Casanova JE, Goldenring JR (2000) Regulation of vesicle trafficking in Madin-Darby canine kidney cells by Rab11a and Rab25. J Biol Chem 275:29138–29146PubMedGoogle Scholar
  75. 75.
    Su T, Bryant DM, Luton F, Verges M, Ulrich SM et al (2010) A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol 12:1143–1153PubMedCentralPubMedGoogle Scholar
  76. 76.
    Powelka AM, Sun J, Li J, Gao M, Shaw LM et al (2004) Stimulation-dependent recycling of integrin beta1 regulated by ARF6 and Rab11. Traffic 5:20–36PubMedGoogle Scholar
  77. 77.
    Fielding AB, Schonteich E, Matheson J, Wilson G, Yu X et al (2005) Rab11–FIP3 and FIP4 interact with Arf6 and the exocyst to control membrane traffic in cytokinesis. EMBO J 24:3389–3399PubMedCentralPubMedGoogle Scholar
  78. 78.
    Mehta SQ, Hiesinger PR, Beronja S, Zhai RG, Schulze KL et al (2005) Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components. Neuron 46:219–232PubMedGoogle Scholar
  79. 79.
    Wu S, Mehta SQ, Pichaud F, Bellen HJ, Quiocho FA (2005) Sec15 interacts with Rab11 via a novel domain and affects Rab11 localization in vivo. Nat Struct Mol Biol 12:879–885PubMedGoogle Scholar
  80. 80.
    Horgan CP, McCaffrey MW (2009) The dynamic Rab11-FIPs. Biochem Soc Trans 37:1032–1036PubMedGoogle Scholar
  81. 81.
    Brighouse A, Dacks JB, Field MC (2010) Rab protein evolution and the history of the eukaryotic endomembrane system. Cell Mol Life Sci 67(20):3449–3465PubMedCentralPubMedGoogle Scholar
  82. 82.
    Gabernet-Castello C, Dubois KN, Nimmo C, Field MC (2011) Rab11 function in Trypanosoma brucei: identification of conserved and novel interaction partners. Eukaryot Cell 10:1082–1094PubMedCentralPubMedGoogle Scholar
  83. 83.
    McGugan GC Jr, Temesvari LA (2003) Characterization of a Rab11-like GTPase, EhRab11, of Entamoeba histolytica. Mol Biochem Parasitol 129:137–146PubMedGoogle Scholar
  84. 84.
    Mitra BN, Saito-Nakano Y, Nakada-Tsukui K, Sato D, Nozaki T (2007) Rab11B small GTPase regulates secretion of cysteine proteases in the enteric protozoan parasite Entamoeba histolytica. Cell Microbiol 9:2112–2125PubMedGoogle Scholar
  85. 85.
    Saito-Nakano Y, Nakazawa M, Shigeta Y, Takeuchi T, Nozaki T (2001) Identification and characterization of genes encoding novel Rab proteins from Entamoeba histolytica. Mol Biochem Parasitol 116:219–222PubMedGoogle Scholar
  86. 86.
    Seaman MN (2005) Recycle your receptors with retromer. Trends Cell Biol 15:68–75PubMedGoogle Scholar
  87. 87.
    Bonifacino JS, Hurleyb JH (2008) Retromer. Curr Opin Cell Biol 20:427–436PubMedCentralPubMedGoogle Scholar
  88. 88.
    Cullen PJ, Korswagen HC (2011) Sorting nexins provide diversity for retromer-dependent trafficking events. Nat Cell Biol 14:29–37PubMedCentralPubMedGoogle Scholar
  89. 89.
    Reddy JV, Seaman MN (2001) Vps26p, a component of retromer, directs the interactions of Vps35p in endosome-to-Golgi retrieval. Mol Biol Cell 12:3242–3256PubMedCentralPubMedGoogle Scholar
  90. 90.
    Haft CR, de la Luz Sierra M, Bafford R, Lesniak MA, Barr VA, Taylor SI (2000) Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Mol Biol Cell 11:4105–4116PubMedCentralPubMedGoogle Scholar
  91. 91.
    Attar N, Cullen PJ (2010) The retromer complex. Adv Enzyme Regul 50:216–236PubMedGoogle Scholar
  92. 92.
    Strochlic TI, Setty TG, Sitaram A, Burd CG (2007) Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling. J Cell Biol 177:115–125PubMedCentralPubMedGoogle Scholar
  93. 93.
    Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M (2011) SNX27 mediates retromer tubule entry and endosome‑to‑plasma membrane trafficking of signalling receptors. Nat Cell Biol 13:717–723Google Scholar
  94. 94.
    Gokool S, Tattersall D, Seaman MN (2007) EHD1 interacts with retromer to stabilize SNX1 tubules and facilitate endosome-to-Golgi retrieval. Traffic 8:1873–1886PubMedGoogle Scholar
  95. 95.
    Gomez TS, Billadeau DD (2009) A FAM21-containing WASH complex regulates retromerdependent sorting. Dev Cell 17:699–711PubMedCentralPubMedGoogle Scholar
  96. 96.
    Harbour ME, Breusegem SY, Antrobus R, Freeman C, Reid E, Seaman MN (2010) The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J Cell Sci 123:3703–3717PubMedCentralPubMedGoogle Scholar
  97. 97.
    Seaman MN, Harbour ME, Tattersall D, Read E, Bright N (2009) Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J Cell Sci 122:2371–2382PubMedCentralPubMedGoogle Scholar
  98. 98.
    Wassmer T, Attar N, Harterink M, van Weering JR, Traer CJ, Oakley J, Goud B, Stephens DJ, Verkade P, Korswagen HC, Cullen PJ (2009) The retromer coat complex coordinates endosomal sorting and dynein-mediated transport, with carrier recognition by the trans-Golgi network. Dev Cell 17:110–122PubMedCentralPubMedGoogle Scholar
  99. 99.
    Pucadyil TJ, Schmid SL (2009) Conserved functions of membrane active GTPases in coated vesicle formation. Science 325:1217–1220PubMedCentralPubMedGoogle Scholar
  100. 100.
    Koumandou VL, Klute MJ, Herman EK, Nunez-Miguel R, Dacks JB, Field MC (2011) Evolutionary reconstruction of the retromer complex and its function in Trypanosoma brucei. J Cell Sci 124:1496–1509PubMedCentralPubMedGoogle Scholar
  101. 101.
    Loftus B, Anderson I, Davies R, Alsmark UC, Samuelson J, Amedeo P, Roncaglia P, Berriman M, Hirt RP, Mann BJ, Nozaki T, Suh B, Pop M, Duchene M, Ackers J, Tannich E, Leippe M, Hofer M, Bruchhaus I, Willhoeft U, Bhattacharya A, Chillingworth T, Churcher C, Hance Z, Harris B, Harris D, Jagels K, Moule S, Mungall K, Ormond D, Squares R, Whitehead S, Quail MA, Rabbinowitsch E, Norbertczak H, Price C, Wang Z, Guillén N, Gilchrist C, Stroup SE, Bhattacharya S, Lohia A, Foster PG, Sicheritz-Ponten T, Weber C, Singh U, Mukherjee C, El-Sayed NM, Petri WA Jr, Clark CG, Embley TM, Barrell B, Fraser CM, Hall N (2005) The genome of the protist parasite Entamoeba histolytica. Nature (Lond) 433:865–868Google Scholar
  102. 102.
    Nothwehr SF, Ha SA, Bruinsma P (2000) Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p. J Cell Biol 151:297–310PubMedCentralPubMedGoogle Scholar
  103. 103.
    Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS (2004) Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J Cell Biol 165:123–133PubMedCentralPubMedGoogle Scholar
  104. 104.
    Kim E, Lee Y, Lee HJ, Kim JS, Song BS, Huh JW, Lee SR, Kim SU, Kim SH, Hong Y, Shim I, Chang KT (2010) Implication of mouse Vps26b-Vps29-Vps35 retromer complex in sortilin trafficking. Biochem Biophys Res Commun 403:167–171PubMedGoogle Scholar
  105. 105.
    Yamazaki M, Shimada T, Takahashi H, Tamura K, Kondo M, Nishimura M, Hara-Nishimura I (2008) Arabidopsis VPS35, a retromer component, is required for vacuolar protein sorting and involved in plant growth and leaf senescence. Plant Cell Physiol 49:142–156PubMedGoogle Scholar
  106. 106.
    Seaman MN, Williams HP (2002) Identification of the functional domains of yeast sorting nexins Vps5p and Vps17p. Mol Biol Cell 13:2826–2840PubMedCentralPubMedGoogle Scholar
  107. 107.
    Habermann B (2004) The BAR-domain family of proteins: a case of bending and binding? EMBO Rep 5:250–255PubMedCentralPubMedGoogle Scholar
  108. 108.
    Rawlings ND, Barrett AJ (1990) Evolution of proteins of the cystatin superfamily. J Mol Evol 30:60–71PubMedGoogle Scholar
  109. 109.
    Kordis D, Turk V (2009) Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes. BMC Evol Biol 9:266PubMedCentralPubMedGoogle Scholar
  110. 110.
    Martínez M, Cambra I, González-Melendi P, Santamaría ME, Díaz I (2012) C1A cysteine-proteases and their inhibitors in plants. Physiol Plant 145:85–94PubMedGoogle Scholar
  111. 111.
    Volpicella M, Leoni C, Costanza A, De Leo F, Gallerani R, Ceci LR (2011) Cystatins, serpins and other families of protease inhibitors in plants. Curr Protein Pept Sci 12:386–398PubMedGoogle Scholar
  112. 112.
    Pierre P, Mellman I (1998) Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell 93:1135–1145PubMedGoogle Scholar
  113. 113.
    Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E (2007) Cystatin C inhibits amyloid-beta deposition in Alzheimer’s disease mouse models. Nat Genet 39:1440–1442PubMedGoogle Scholar
  114. 114.
    Björck L, Grubb A, Kjellén L (1990) Cystatin C, a human proteinase inhibitor, blocks replication of herpes simplex virus. J Virol 64:941–943PubMedCentralPubMedGoogle Scholar
  115. 115.
    van der Linde K, Hemetsberger C, Kastner C, Kaschani F, van der Hoorn RA, Kumlehn J, Doehlemann G (2012) A maize cystatin suppresses host immunity by inhibiting apoplastic cysteine proteases. Plant Cell 24:1285–1300PubMedCentralPubMedGoogle Scholar
  116. 116.
    Monteiro AC, Abrahamson M, Lima AP, Vannier-Santos MA, Scharfstein J (2001) Identification, characterization and localization of chagasin, a tight-binding cysteine protease inhibitor in Trypanosoma cruzi. J Cell Sci 114:3933–3942PubMedGoogle Scholar
  117. 117.
    Riekenberg S, Witjes B, Sarić M, Bruchhaus I, Scholze H (2005) Identification of EhICP1, a chagasin-like cysteine protease inhibitor of Entamoeba histolytica. FEBS Lett 579:1573–1578PubMedGoogle Scholar
  118. 118.
    Sato D, Nakada-Tsukui K, Okada M, Nozaki T (2006) Two cysteine protease inhibitors, EhICP1 and 2, localized in distinct compartments, negatively regulate secretion in Entamoeba histolytica. FEBS Lett 580:5306–5312PubMedGoogle Scholar
  119. 119.
    Besteiro S, Coombs GH, Mottram JC (2004) A potential role for ICP, a Leishmanial inhibitor of cysteine peptidases, in the interaction between host and parasite. Mol Microbiol 54:1224–1236PubMedCentralPubMedGoogle Scholar
  120. 120.
    Sanderson SJ, Westrop GD, Scharfstein J, Mottram JC, Coombs GH (2003) Functional conservation of a natural cysteine peptidase inhibitor in protozoan and bacterial pathogens. FEBS Lett 542:12–16PubMedGoogle Scholar
  121. 121.
    Pandey KC, Singh N, Arastu-Kapur S, Bogyo M, Rosenthal PJ (2006) Falstatin, a cysteine protease inhibitor of Plasmodium falciparum, facilitates erythrocyte invasion. PLoS Pathog 2(11):e117PubMedCentralPubMedGoogle Scholar
  122. 122.
    Rennenberg A, Lehmann C, Heitmann A, Witt T, Hansen G, Nagarajan K, Deschermeier C, Turk V, Hilgenfeld R, Heussler VT (2010) Exoerythrocytic Plasmodium parasites secrete a cysteine protease inhibitor involved in sporozoite invasion and capable of blocking cell death of host hepatocytes. PLoS Pathog 6(3):e1000825PubMedCentralPubMedGoogle Scholar
  123. 123.
    Kang JM, Ju HL, Yu JR, Sohn WM, Na BK (2012) Cryptostatin, a chagasin-family cysteine protease inhibitor of Cryptosporidium parvum. Parasitology 139:1029–1037PubMedGoogle Scholar
  124. 124.
    Rigden D, Mosolov VV, Galperin MY (2002) Sequence conservation in the chagasin family suggests a common trend in cysteine proteinase binding by unrelated protein inhibitors. Protein Sci 11:1971–1977PubMedCentralPubMedGoogle Scholar
  125. 125.
    Katunuma N, Kominami E (1995) Structure, properties, mechanisms, and assays of cysteine protease inhibitors: cystatins and E-64 derivatives. Methods Enzymol 251:382–397PubMedGoogle Scholar
  126. 126.
    Salmon D, do Aido-Machado R, Diehl A, Leidert M, Schmetzer O, de Lima AP, Scharfstein J, Oschkinat H, Pires JR (2006) Solution structure and backbone dynamics of the Trypanosoma cruzi cysteine protease inhibitor chagasin. J Mol Biol 357:1511–1521PubMedGoogle Scholar
  127. 127.
    Smith BO, Picken NC, Westrop GD, Bromek K, Mottram JC, Coombs GH (2006) The structure of Leishmania mexicana ICP provides evidence for convergent evolution of cysteine peptidase inhibitors. J Biol Chem 281:5821–5828PubMedCentralPubMedGoogle Scholar
  128. 128.
    Santos CC, Sant’Anna C, Terres A, Cunha-e-Silva NL, de Scharfstein J, Lima A, APC (2005) Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells. J Cell Sci 118:901–915PubMedGoogle Scholar
  129. 129.
    Sarić M, Irmerb H, Eckerta D, Bärb A-K, Bruchhaus I, Scholzea H (2012) The cysteine protease inhibitors EhICP1 and EhICP2 perform different tasks in the regulation of endogenous protease activity in trophozoites of Entamoeba histolytica. Protist 163:116–128PubMedGoogle Scholar
  130. 130.
    Casados-Vázquez LE, Lara-González S, Brieba LG (2011) Crystal structure of the cysteine protease inhibitor 2 from Entamoeba histolytica: functional convergence of a common protein fold. Gene (Amst) 471:45–52Google Scholar
  131. 131.
    Olson LJ, Peterson FC, Castonguay A, Bohnsack RN, Kudo M, Gotschall RR, Canfield WM, Volkman BF, Dahms NM (2010) Structural basis for recognition of phosphodiester-containing lysosomal enzymes by the cation-independent mannose 6-phosphate receptor. Proc Natl Acad Sci USA 107:12493–12498PubMedCentralPubMedGoogle Scholar
  132. 132.
    Hermey G (2009) The Vps10p-domain receptor family. Cell Mol Life Sci 66:2677–2689PubMedGoogle Scholar
  133. 133.
    Quistgaard EM, Madsen P, Grøftehauge MK, Nissen P, Petersen CM, Thirup SS (2009) Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain. Nat Struct Mol Biol 16:96–98PubMedGoogle Scholar
  134. 134.
    Shinshi H, Wenzler H, Neuhaus JM, Felix G, Hofsteenge J, Meins F (1988) Evidence for N- and C-terminal processing of a plant defense-related enzyme: Primary structure of tobacco prepro-beta-1,3- glucanase. Proc Natl Acad Sci USA 85:5541–5545PubMedCentralPubMedGoogle Scholar
  135. 135.
    Voelker TA, Herman EM, Chrispeels MJ (1989) In vitro mutated phytohemagglutinin genes expressed in tobacco seeds: role of glycans in protein targeting and stability. Plant Cell 1:95–104PubMedCentralPubMedGoogle Scholar
  136. 136.
    Cao X, Rogers SW, Butler J, Beevers L, Rogers JC (2000) Structural requirements for ligand binding by a probable plant vacuolar sorting receptor. Plant Cell 12:493–506PubMedCentralPubMedGoogle Scholar
  137. 137.
    Watanabe E, Shimada T, Kuroyanagi M, Nishimura M, Hara-Nishimura I (2002) Calcium-mediated association of a putative vacuolar sorting receptor PV72 with a propeptide of 2S albumin. J Biol Chem 277:8708–8715PubMedGoogle Scholar
  138. 138.
    Kirsch T, Paris N, Butler JM, Beevers L, Rogers JC (1994) Purification and initial characterization of a potential plant vacuolar targeting receptor. Proc Natl Acad Sci USA 91:3403–3407PubMedCentralPubMedGoogle Scholar
  139. 139.
    Watanabe E, Shimada T, Tamura K, Matsushima R, Koumoto Y, Nishimura M, Hara-Nishimura I (2004) An ER-localized form of PV72, a seed-specific vacuolar sorting receptor, interferes the transport of an NPIR-containing proteinase in Arabidopsis leaves. Plant Cell Physiol 45:9–17PubMedGoogle Scholar
  140. 140.
    Suen PK, Shen J, Sun SSM, Jiang L (2010) Expression and characterization of two functional vacuolar sorting receptor (VSR) proteins, BP-80 and AtVSR4 from culture media of transgenic tobacco BY-2 cells. Plant Sci 179:68–76Google Scholar
  141. 141.
    Dahms NM, Olson LJ, Kim JJ (2008) Strategies for carbohydrate recognition by the mannose 6-phosphate receptors. Glycobiology 18:664–678PubMedCentralPubMedGoogle Scholar
  142. 142.
    Bruchhaus I, Jacobs T, Leippe M, Tannich E (1996) Entamoeba histolytica and Entamoeba dispar: differences in numbers and expression of cysteine proteinase genes. Mol Microbiol 22:255–263PubMedGoogle Scholar
  143. 143.
    Willhoeft U, Buss H, Tannich E (1999) Analysis of cDNA expressed sequence tags from Entamoeba histolytica: identification of two highly abundant polyadenylated transcripts with no overt open reading frames. Protist 150:61–70PubMedGoogle Scholar
  144. 144.
    Ankri S, Stolarsky T, Bracha R, Padilla-Vaca F, Mirelman D (1999) Antisense inhibition of expression of cysteine proteinases affects Entamoeba histolytica-induced formation of liver abscess in hamsters. Infect Immun 67:421–422PubMedCentralPubMedGoogle Scholar
  145. 145.
    Nakatsu F, Ohno H (2003) Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct Funct 28:419–429PubMedGoogle Scholar
  146. 146.
    Furukawa A, Nakada-Tsukui K, Nozaki T (2013) Cysteine protease-binding protein family 6 mediates the trafficking of amylases to phagosomes in the enteric protozoan Entamoeba histolytica. Infect Immun 81(5):1820–1829PubMedCentralPubMedGoogle Scholar
  147. 147.
    Furukawa A, Nakada-Tsukui K, Nozaki T (2012) Novel transmembrane receptor involved in phagosome transport of lysozymes and β-hexosaminidase in the enteric protozoan Entamoeba histolytica. PLoS Pathog 8:e1002539PubMedCentralPubMedGoogle Scholar
  148. 148.
    Marumo K, Nakada-Tsukui K, Tomii K, Nozaki T. (2014) Ligand heterogeneity of the cysteine protease binding protein family in the parasitic protist Entamoeba histolytica. Int J Parasitol 44:625–635.Google Scholar
  149. 149.
    Penuliar GM, Furukawa A, Nakada-Tsukui K, Husain A, Sato D, Nozaki T (2012) Transcriptional and functional analysis of trifluoromethionine resistance in Entamoeba histolytica. J Antimicrob Chemother 67:375–386PubMedGoogle Scholar
  150. 150.
    Riekenberg S, Flockenhaus B, Vahrmann A, Müller MC, Leippe M, Kiess M, Scholze H (2004) The beta-N-acetylhexosaminidase of Entamoeba histolytica is composed of two homologous chains and has been localized to cytoplasmic granules. Mol Biochem Parasitol 138:217–225PubMedGoogle Scholar
  151. 151.
    Kornfeld S (1992) Structure and function of the mannose 6-phosphate/ insulin-like growth factor II receptors. Annu Rev Biochem 61:307–330PubMedGoogle Scholar
  152. 152.
    Wilson DW, Lewis MJ, Pelham HR (1993) pH-dependent binding of KDEL to its receptor in vitro. J Biol Chem 268:7465–7468PubMedGoogle Scholar
  153. 153.
    Scheel AA, Pelham HR (1996) Purification and characterization of the human KDEL receptor. Biochemistry 35:10203–10209PubMedGoogle Scholar
  154. 154.
    Raha S, Dalal B, Biswas S, Biswas BB (1994) Myo-inositol trisphosphate-mediated calcium release from internal stores of Entamoeba histolytica. Mol Biochem Parasitol 65:63–71PubMedGoogle Scholar
  155. 155.
    Yousuf MA, Mi-ichi F, Nakada-Tsukui K, Nozaki T (2010) Localization and targeting of an unusual pyridine nucleotide transhydrogenase in Entamoeba histolytica. Eukaryot Cell 9:926–933PubMedCentralPubMedGoogle Scholar
  156. 156.
    Weston CJ, White SA, Jackson JB (2001) The unusual transhydrogenase of Entamoeba histolytica. FEBS Lett 488:51–54PubMedGoogle Scholar
  157. 157.
    Freeze HH, Miller AL, Kaplan A (1980) Acid hydrolases from Dictyostelium discoideum contain phosphomannosyl recognition markers. J Biol Chem 255:11081–11084PubMedGoogle Scholar
  158. 158.
    Lang L, Couso R, Kornfeld S (1986) Glycoprotein phosphorylation in simple eucaryotic organisms. Identification of UDP-GlcNAc:glycoprotein N-acetylglucosamine-1-phosphotransferase activity and analysis of substrate specificity. J Biol Chem 261:6320–6325PubMedGoogle Scholar
  159. 159.
    Freeze HH (1990) Glycoproteins in Dictyostelium. Dev Genet 11:453–462Google Scholar
  160. 160.
    Souza GM, Mehta DP, Lammertz M, Rodriguez-Paris J, Wu R, Cardelli JA, Freeze HH (1997) Dictyostelium lysosomal proteins with different sugar modifications sort to functionally distinct compartments. J Cell Sci 110:2239–2248PubMedGoogle Scholar
  161. 161.
    Dennes A, Cromme C, Suresh K, Kumar NS, Eble JA, Hahnenkamp A, Pohlmann R (2005) The novel Drosophila lysosomal enzyme receptor protein mediates lysosomal sorting in mammalian cells and binds mammalian and Drosophila GGA adaptors. J Biol Chem 280:12849–12857PubMedGoogle Scholar
  162. 162.
    Whyte JR, Munro S (2001) A yeast homolog of the mammalian mannose 6-phosphate receptors contributes to the sorting of vacuolar hydrolases. Curr Biol 11:1074–1078PubMedGoogle Scholar
  163. 163.
    Rivero MR, Miras SL, Feliziani C, Zamponi N, Quiroga R, Hayes SF, Rópolo AS, Touz MC (2012) Vacuolar protein sorting receptor in Giardia lamblia. PLoS One 7(8):e43712PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Department of ParasitologyNational Institute of Infectious DiseasesTokyoJapan
  2. 2.Graduate School of Life and Environmental SciencesUniversity of TsukubaIbarakiJapan

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