The Gp78 ubiquitin ligase: probing endoplasmic reticulum complexity

  • 634 Accesses

  • 7 Citations


The endoplasmic reticulum (ER) has been classically divided, based on electron microscopy analysis, into parallel ribosome-studded rough ER sheets and a tubular smooth ER network. Recent studies have identified molecular constituents of the ER, the reticulons and DP1, that drive ER tubule formation and whose expression determines expression of ER sheets and tubules and thereby rough and smooth ER. However, segregation of the ER into only two domains remains simplistic and multiple functionally distinct ER domains necessarily exist. In this review, we will discuss the sub-organization of the ER in different domains focusing on the localization and role of the gp78 ubiquitin ligase in the mitochondria-associated smooth ER and on the evidence for a quality control ERAD domain.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. Ballar P, Shen Y, Yang H, Fang S (2006) The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem 281(46):35359–35368

  2. Bar-Nun S (2005) The role of p97/Cdc48p in endoplasmic reticulum-associated degradation: from the immune system to yeast. Curr Top Microbiol Immunol 300:95–125

  3. Baumann O, Walz B (2001) Endoplasmic reticulum of animal cells and its organization into structural and functional domains. Int Rev Cytol 205:149–214

  4. Bebok Z, Mazzochi C, King SA, Hong JS, Sorscher EJ (1998) The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. J Biol Chem 273(45):29873–29878

  5. Benlimame N, Simard D, Nabi IR (1995) Autocrine motility factor receptor is a marker for a distinct membranous tubular organelle. J Cell Biol 129(2):459–471

  6. Benlimame N, Le PU, Nabi IR (1998) Localization of autocrine motility factor receptor to caveolae and clathrin-independent internalization of its ligand to smooth endoplasmic reticulum. Mol Biol Cell 9(7):1773–1786

  7. Bernales S, McDonald KL, Walter P (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4(12):e423. doi:10.1371/journal.pbio.0040423

  8. Bernardi KM, Forster ML, Lencer WI, Tsai B (2008) Derlin-1 facilitates the retro-translocation of cholera toxin. Mol Biol Cell 19(3):877–884. doi:E07-08-0755[pii]10.1091/mbc.E07-08-0755

  9. Bernardi KM, Williams JM, Kikkert M, van Voorden S, Wiertz EJ, Ye Y, Tsai B (2010) The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation. Mol Biol Cell 21(1):140–151. doi:10.1091/mbc.E09-07-0586

  10. Berridge MJ (2002) The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32(5–6):235–249. doi:S0143416002001823

  11. Bruderer RM, Brasseur C, Meyer HH (2004) The AAA ATPase p97/VCP interacts with its alternative co-factors, Ufd1-Npl4 and p47, through a common bipartite binding mechanism. J Biol Chem 279(48):49609–49616. doi:10.1074/jbc.M408695200M408695200

  12. Carvalho P, Stanley AM, Rapoport TA (2010) Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 143(4):579–591. doi:S0092-8674(10)01198-0[pii]10.1016/j.cell.2010.10.028

  13. Cerqua C, Anesti V, Pyakurel A, Liu D, Naon D, Wiche G, Baffa R, Dimmer KS, Scorrano L (2010) Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition. EMBO Rep 11(11):854–860. doi:10.1038/embor.2010.151

  14. Chao JT, Loewen JR (2010) ER Junctions. In: Nabi IR (ed) Cellular domains. Wiley Press

  15. Chen Y, Le Caherec F, Chuck SL (1998) Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex. J Biol Chem 273(19):11887–11894

  16. Chevet E, Wong HN, Gerber D, Cochet C, Fazel A, Cameron PH, Gushue JN, Thomas DY, Bergeron JJ (1999) Phosphorylation by CK2 and MAPK enhances calnexin association with ribosomes. EMBO J 18(13):3655–3666. doi:10.1093/emboj/18.13.3655

  17. Chin DJ, Luskey KL, Anderson RG, Faust JR, Goldstein JL, Brown MS (1982) Appearance of crystalloid endoplasmic reticulum in compactin-resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A 79(4):1185–1189

  18. Chiu CG, St-Pierre P, Nabi IR, Wiseman SM (2008) Autocrine motility factor receptor: a clinical review. Expert Rev Anticancer Ther 8(2):207–217. doi:10.1586/14737140.8.2.207

  19. Dalal S, Rosser MF, Cyr DM, Hanson PI (2004) Distinct roles for the AAA ATPases NSF and p97 in the secretory pathway. Mol Biol Cell 15(2):637–648. doi:10.1091/mbc.E03-02-0097E03-02-0097

  20. de Brito OM, Scorrano L (2008) Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion. Antioxid Redox Signal 10(3):621–633. doi:10.1089/ars.2007.1934

  21. de Virgilio M, Weninger H, Ivessa NE (1998) Ubiquitination is required for the retro-translocation of a short-lived luminal endoplasmic reticulum glycoprotein to the cytosol for degradation by the proteasome. J Biol Chem 273(16):9734–9743

  22. DeBose-Boyd RA (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18(6):609–621. doi:10.1038/cr.2008.61

  23. Dejgaard K, Theberge JF, Heath-Engel H, Chevet E, Tremblay ML, Thomas DY (2010) Organization of the Sec61 translocon, studied by high resolution native electrophoresis. J Proteome Res 9(4):1763–1771. doi:10.1021/pr900900x

  24. Dixit G, Mikoryak C, Hayslett T, Bhat A, Draper RK (2008) Cholera toxin up-regulates endoplasmic reticulum proteins that correlate with sensitivity to the toxin. Exp Biol Med (Maywood) 233(2):163–175. doi:10.3181/0705-RM-132

  25. Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4(3):181–191

  26. Fang S, Ferrone M, Yang C, Jensen JP, Tiwari S, Weissman AM (2001) The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A 98(25):14422–14427

  27. Frenkel Z, Shenkman M, Kondratyev M, Lederkremer GZ (2004) Separate roles and different routing of calnexin and ERp57 in endoplasmic reticulum quality control revealed by interactions with asialoglycoprotein receptor chains. Mol Biol Cell 15(5):2133–2142. doi:10.1091/mbc.E03-12-0899E03-12-0899

  28. Friedman JR, Lackner LL, West M, Dibenedetto JR, Nunnari J, Voeltz GK (2011) ER Tubules mark sites of mitochondrial division. Science. doi:10.1126/science.1207385

  29. Gilchrist A, Au CE, Hiding J, Bell AW, Fernandez-Rodriguez J, Lesimple S, Nagaya H, Roy L, Gosline SJC, Hallett M, Paiement J, Kearney RE, Nilsson T, Bergeron JJM (2006) Quantitative proteomics analysis of the secretory pathway. Cell 127(6):1265–1281

  30. Goetz JG, Genty H, St-Pierre P, Dang T, Joshi B, Sauve R, Vogl W, Nabi IR (2007) Reversible interactions between smooth domains of the endoplasmic reticulum and mitochondria are regulated by physiological cytosolic Ca2+ levels. J Cell Sci 120(Pt 20):3553–3564

  31. Hebert DN, Bernasconi R, Molinari M (2010) ERAD substrates: which way out? Semin Cell Dev Biol 21(5):526–532. doi:10.1016/j.semcdb.2009.12.007

  32. Hu J, Shibata Y, Voss C, Shemesh T, Li Z, Coughlin M, Kozlov MM, Rapoport TA, Prinz WA (2008) Membrane proteins of the endoplasmic reticulum induce high-curvature tubules. Science 319(5867):1247–1250. doi:319/5867/1247[pii]10.1126/science.1153634

  33. Iinuma T, Aoki T, Arasaki K, Hirose H, Yamamoto A, Samata R, Hauri HP, Arimitsu N, Tagaya M, Tani K (2009) Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains. J Cell Sci 122(Pt 10):1680–1690. doi:10.1242/jcs.036103

  34. Jones AL, Armstrong DT (1965) Increased cholesterol biosynthesis following phenobarbital induced hypertrophy of agranular endoplasmic reticulum in liver. Proc Soc Exp Biol Med 119(4):1136–1139

  35. Kamhi-Nesher S, Shenkman M, Tolchinsky S, Fromm SV, Ehrlich R, Lederkremer GZ (2001) A novel quality control compartment derived from the endoplasmic reticulum. Mol Biol Cell 12(6):1711–1723

  36. Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325(5939):477–481. doi:10.1126/science.1175088

  37. Lederkremer GZ (2009) Glycoprotein folding, quality control and ER-associated degradation. Curr Opin Struct Biol 19(5):515–523. doi:10.1016/

  38. Liao W, Yeung SC, Chan L (1998) Proteasome-mediated degradation of apolipoprotein B targets both nascent peptides cotranslationally before translocation and full-length apolipoprotein B after translocation into the endoplasmic reticulum. J Biol Chem 273(42):27225–27230

  39. Lynes EM, Simmen T (2011) Urban planning of the endoplasmic reticulum (ER): how diverse mechanisms segregate the many functions of the ER. Biochim Biophys Acta 1813(10):1893–1905. doi:10.1016/j.bbamcr.2011.06.011

  40. Michalak M, Groenendyk J, Szabo E, Gold LI, Opas M (2009) Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 417(3):651–666. doi:10.1042/BJ20081847

  41. Mori A, Yamashita S, Uchino K, Suga T, Ikeda T, Takamatsu K, Ishizaki M, Koide T, Kimura E, Mita S, Maeda Y, Hirano T, Uchino M (2011) Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation. Neurochem Int 58(3):344–353. doi:10.1016/j.neuint.2010.12.010

  42. Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata AK (2008) Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell 19(4):1328–1336. doi:10.1091/mbc.E07-06-0601

  43. Myhill N, Lynes EM, Nanji JA, Blagoveshchenskaya AD, Fei H, Carmine Simmen K, Cooper TJ, Thomas G, Simmen T (2008) The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell 19(7):2777–2788. doi:E07-10.1091/mbc.E07-10-0995

  44. Nakatsukasa K, Huyer G, Michaelis S, Brodsky JL (2008) Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132(1):101–112. doi:10.1016/j.cell.2007.11.023

  45. Orci L, Brown MS, Goldstein JL, Garcia-Segura LM, Anderson RG (1984) Increase in membrane cholesterol: a possible trigger for degradation of HMG CoA reductase and crystalloid endoplasmic reticulum in UT-1 cells. Cell 36(4):835–845. doi:0092-8674(84)90033-3

  46. Paquet ME, Cohen-Doyle M, Shore GC, Williams DB (2004) Bap29/31 influences the intracellular traffic of MHC class I molecules. J Immunol 172(12):7548–7555. doi:172/12/7548

  47. Pearce MM, Wang Y, Kelley GG, Wojcikiewicz RJ (2007) SPFH2 mediates the endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors and other substrates in mammalian cells. J Biol Chem 282(28):20104–20115. doi:10.1074/jbc.M701862200

  48. Perkins G, Renken C, Martone ME, Young SJ, Ellisman M, Frey T (1997) Electron tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts. J Struct Biol 119(3):260–272. doi:10.1006/jsbi.1997.3885

  49. Petaja-Repo UE, Hogue M, Laperriere A, Bhalla S, Walker P, Bouvier M (2001) Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome. J Biol Chem 276(6):4416–4423. doi:10.1074/jbc.M007151200M007151200

  50. Qian SB, Ott DE, Schubert U, Bennink JR, Yewdell JW (2002) Fusion proteins with COOH-terminal ubiquitin are stable and maintain dual functionality in vivo. J Biol Chem 277(41):38818–38826. doi:10.1074/jbc.M205547200M205547200

  51. Raposo G, van Santen HM, Leijendekker R, Geuze HJ, Ploegh HL (1995) Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment. J Cell Biol 131(6 Pt 1):1403–1419

  52. Registre M, Goetz JG, St Pierre P, Pang H, Lagace M, Bouvier M, Le PU, Nabi IR (2004) The gene product of the gp78/AMFR ubiquitin E3 ligase cDNA is selectively recognized by the 3F3A antibody within a subdomain of the endoplasmic reticulum. Biochem Biophys Res Commun 320(4):1316–1322

  53. Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA, Pozzan T (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280(5370):1763–1766

  54. Roderick HL, Lechleiter JD, Camacho P (2000) Cytosolic phosphorylation of calnexin controls intracellular Ca(2+) oscillations via an interaction with SERCA2b. J Cell Biol 149(6):1235–1248

  55. Rutledge AC, Qiu W, Zhang R, Kohen-Avramoglu R, Nemat-Gorgani N, Adeli K (2009) Mechanisms targeting apolipoprotein B100 to proteasomal degradation: evidence that degradation is initiated by BiP binding at the N terminus and the formation of a p97 complex at the C terminus. Arterioscler Thromb Vasc Biol 29(4):579–585. doi:10.1161/ATVBAHA.108.181859

  56. Sato R, Imanaka T, Takatsuki A, Takano T (1990) Degradation of newly synthesized apolipoprotein B-100 in a pre-Golgi compartment. J Biol Chem 265(20):11880–11884

  57. Schwieger I, Lautz K, Krause E, Rosenthal W, Wiesner B, Hermosilla R (2008) Derlin-1 and p97/valosin-containing protein mediate the endoplasmic reticulum-associated degradation of human V2 vasopressin receptors. Mol Pharmacol 73(3):697–708. doi:10.1124/mol.107.040931

  58. Scott DC, Schekman R (2008) Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins. J Cell Biol 181(7):1095–1105. doi:10.1083/jcb.200804053

  59. Shibata Y, Voss C, Rist JM, Hu J, Rapoport TA, Prinz WA, Voeltz GK (2008) The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J Biol Chem 283(27):18892–18904. doi:10.1074/jbc.M800986200

  60. Shibata Y, Shemesh T, Prinz WA, Palazzo AF, Kozlov MM, Rapoport TA (2010) Mechanisms determining the morphology of the peripheral ER. Cell 143(5):774–788. doi:10.1016/j.cell.2010.11.007

  61. Shore GC, Tata JR (1977) Two fractions of rough endoplasmic reticulum from rat liver. I. Recovery of rapidly sedimenting endoplasmic reticulum in association with mitochondria. J Cell Biol 72(3):714–725

  62. Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM, Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24(4):717–729. doi:10.1038/sj.emboj.7600559

  63. Snapp EL (2009) Fluorescent proteins: a cell biologist’s user guide. Trends Cell Biol 19(11):649–655. doi:10.1016/j.tcb.2009.08.002

  64. Snapp EL, Sharma A, Lippincott-Schwartz J, Hegde RS (2006) Monitoring chaperone engagement of substrates in the endoplasmic reticulum of live cells. Proc Natl Acad Sci U S A 103(17):6536–6541. doi:10.1073/pnas.0510657103

  65. Sparkes I, Tolley N, Aller I, Svozil J, Osterrieder A, Botchway S, Mueller C, Frigerio L, Hawes C (2010) Five Arabidopsis reticulon isoforms share endoplasmic reticulum location, topology, and membrane-shaping properties. Plant Cell 22(4):1333–1343. doi:10.1105/tpc.110.074385

  66. Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175(6):901–911. doi:10.1083/jcb.200608073

  67. Terasaki M, Runft LL, Hand AR (2001) Changes in organization of the endoplasmic reticulum during Xenopus oocyte maturation and activation. Mol Biol Cell 12(4):1103–1116

  68. Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265(13):7248–7256

  69. Vedrenne C, Hauri HP (2006) Morphogenesis of the endoplasmic reticulum: beyond active membrane expansion. Traffic 7(6):639–646. doi:10.1111/j.1600-0854.2006.00419.x

  70. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9(12):944–957. doi:10.1038/nrm2546

  71. Voeltz GK, Prinz WA (2007) Sheets, ribbons and tubules—how organelles get their shape. Nat Rev Mol Cell Biol 8(3):258–264. doi:10.1038/nrm2119

  72. Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA (2006) A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124(3):573–586. doi:10.1016/j.cell.2005.11.047

  73. Wakana Y, Takai S, Nakajima K, Tani K, Yamamoto A, Watson P, Stephens DJ, Hauri HP, Tagaya M (2008) Bap31 is an itinerant protein that moves between the peripheral endoplasmic reticulum (ER) and a juxtanuclear compartment related to ER-associated degradation. Mol Biol Cell 19(5):1825–1836. doi:10.1091/mbc.E07-08-0781

  74. Wang HJ, Benlimame N, Nabi I (1997) The AMF-R tubule is a smooth ilimaquinone-sensitive subdomain of the endoplasmic reticulum. J Cell Sci 110(Pt 24):3043–3053

  75. Wang HJ, Guay G, Pogan L, Sauve R, Nabi IR (2000) Calcium regulates the association between mitochondria and a smooth subdomain of the endoplasmic reticulum. J Cell Biol 150(6):1489–1498

  76. Wang B, Heath-Engel H, Zhang D, Nguyen N, Thomas DY, Hanrahan JW, Shore GC (2008) BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex. Cell 133(6):1080–1092. doi:10.1016/j.cell.2008.04.042

  77. Wesche J, Rapak A, Olsnes S (1999) Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol. J Biol Chem 274(48):34443–34449

  78. Willer M, Forte GM, Stirling CJ (2008) Sec61p is required for ERAD-L: genetic dissection of the translocation and ERAD-L functions of Sec61P using novel derivatives of CPY. J Biol Chem 283(49):33883–33888. doi:10.1074/jbc.M803054200

  79. Wojcik C, Yano M, DeMartino GN (2004) RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis. J Cell Sci 117(Pt 2):281–292

  80. Zhou M, Schekman R (1999) The engagement of Sec61p in the ER dislocation process. Mol Cell 4(6):925–934. doi:S1097-2765(00)80222-1

Download references


Work on this project is supported by a grant from the Canadian Institutes for Health Research (CIHR MT-15132). PSP is the recipient of a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Ivan R. Nabi.

Additional information

Handling Editor: Geoffrey O. Wasteneys

Electronic supplementary material

Below is the link to the electronic supplementary material.

(MPG 1494 kb)


(MPG 1494 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

St. Pierre, P., Nabi, I.R. The Gp78 ubiquitin ligase: probing endoplasmic reticulum complexity. Protoplasma 249, 11–18 (2012) doi:10.1007/s00709-011-0344-8

Download citation


  • Ubiquitin ligase
  • Endoplasmic reticulum
  • Mitochondria
  • ERAD