Abstract
Endoplasmic reticulum-associated protein degradation (ERAD) is a cellular process that targets short-lived resident proteins and aberrant secretory proteins to the proteasome for degradation. ERAD is essential for maintaining the homeostasis of the secretory pathway, as the retention of misfolded proteins in the ER can lead to several diseases. The budding yeast Saccharomyces cerevisiae has been used as a model organism for dissecting the molecular components of the ERAD pathway. This review describes the multi-subunit protein machineries in the ER membrane that are involved in the recognition of misfolded proteins, their ubiquitylation, and their retro-translocation to the cytosol and delivery to the proteasome. Most of the yeast components are conserved in humans and the analysis of the function in ERAD of the yeast counterparts has been crucial in elucidating the mechanisms responsible for human disorders.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Ahner, A., and Brodsky, J.L. (2004). Checkpoints in ER-associated degradation: excuse me, which way to the proteasome? Trends Cell Biol. 14:474–478.
Alam, S.L., Sun, J., Payne, M., et al. (2004). Ubiquitin interactions of NZF zinc fingers. EMBO J. 23:1411–1421.
Alrefai, W.A., and Gill, R.K. (2007). Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm. Res. 24:1803–1823.
Amano, T., Yamasaki, S., Yagishita, N., et al. (2003). Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev. 17:2436–2449.
Anelli, T., and Sitia, R. (2008). Protein quality control in the early secretory pathway. EMBO J. 27:315–327.
Arteaga, M.F., Wang, L., Ravid, T., et al. (2006). An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc. Natl. Acad. Sci. USA. 103:11178–11183.
Balzi, E., Wang, M., Leterme, S., et al. (1994). PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J. Biol. Chem. 269:2206–2214.
Bays, N.W., Gardner, R.G., Seelig, L.P., et al. (2001a). Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat. Cell Biol. 3:24–29.
Bays, N.W., Wilhovsky, S.K., Goradia, A., et al. (2001b). HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol. Biol. Cell 12:4114–4128.
Bernales, S., Schuck, S., Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3:285–287.
Bernardi, K.M., Forster, M.L., Lencer, W.I. et al. (2008). Derlin-1 facilitates the retro-translocation of cholera toxin. Mol. Biol. Cell 19:877–884.
Bhamidipati, A., Denic, V., Quan, E.M. et al. (2005). Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol. Cell 19:741–751.
Biederer, T., Volkwein, C., Sommer, T. (1997). Role of Cue1p in ubiquitination and degradation at the ER surface. Science 278:1806–1809.
Bissinger, P.H., and Kuchler, K. (1994). Molecular cloning and expression of the Saccharomyces cerevisiae STS1 gene product. A yeast ABC transporter conferring mycotoxin resistance. J. Biol. Chem. 269:4180–4186.
Braun, S., Matuschewski, K., Rape, M., et al. (2002). Role of the ubiquitin-selective CDC48 (UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21:615–621.
Brodsky, J.L. (1996). Post-translational protein translocation: not all hsc70s are created equal. Trends Biochem. Sci. 21:122–126.
Bruderer, R.M., Brasseur, C., Meyer, H.H. (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. 279:49609–49616.
Bukau, B., Weissman, J., Horwich, A. (2006). Molecular chaperones and protein quality control. Cell 125:443–451.
Buschhorn, B.A., Kostova, Z., Medicherla, B. et al. (2004). A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett. 577:422–426.
Byrd, J.C., Tarentino, A.L., Maley, F., et al. (1982). Glycoprotein synthesis in yeast. Identification of Man8GlcNAc2 as an essential intermediate in oligosaccharide processing. J. Biol. Chem. 257:14657–14666.
Carvalho, P., Goder, V., Rapoport, T.A. (2006). Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:361–373.
Chapman, R., Sidrauski, C., Walter, P. (1998). Intracellular signaling from the endoplasmic reticulum to the nucleus. Annu. Rev. Cell Dev. Biol. 14:459–485.
Chen, L., and Madura, K. (2002). Rad23 promotes the targeting of proteolytic substrates to the proteasome. Mol. Cell Biol. 22:4902–4913.
Chen, S.Y., Bhargava, A., Mastroberardino, L., et al. (1999). Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc. Natl. Acad. Sci. USA. 96:2514–2519.
Clerc, S., Hirsch, C., Oggier, D.M., et al. (2009). Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J. Cell Biol. 184:159–172.
Cox, J.S., and Walter, P. (1996). A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404.
de Kerchove d’Exaerde, A., Supply, P., Dufour, J.P., et al. (1995). Functional complementation of a null mutation of the yeast Saccharomyces cerevisiae plasma membrane H(+)-ATPase by a plant H(+)-ATPase gene. J. Biol. Chem. 270:23828–23837.
Deak, P.M., and Wolf, D.H. (2001). Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J. Biol. Chem. 276:10663–10669.
Decottignies, A., Evain, A., Ghislain, M. (2004). Binding of Cdc48p to a ubiquitin-related UBX domain from novel yeast proteins involved in intracellular proteolysis and sporulation. Yeast 21:127–139.
De LaBarre, B., and Brunger, A.T. (2003). Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat. Struct. Biol. 10:856–863.
Denic, V., Quan, E.M., Weissman, J.S. (2006). A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126:349–359.
Dolinski, K., Muir, S., Cardenas, M., et al. (1997). All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA. 94:13093–13098.
Dreveny, I., Kondo, H., Uchiyama, K., et al. (2004). Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. EMBO J. 23:1030–1039.
Egner, R., Rosenthal, F.E., Kralli, A., Sanglard, D. et al. (1998). Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. Mol. Biol. Cell 9:523–543.
Ellgaard, L., and Helenius, A. (2003). Quality control in the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol. 4:181–191.
Elsasser, S., Gali, R.R., Schwickart, M., et al. (2002). Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat. Cell Biol. 4:725–730.
Fassio, A., and Sitia, R. (2002). Formation, isomerisation and reduction of disulphide bonds during protein quality control in the endoplasmic reticulum. Histochem. Cell Biol. 117:151–157.
Finger, A., Knop, M., Wolf, D.H. (1993). Analysis of two mutated vacuolar proteins reveals a degradation pathway in the endoplasmic reticulum or a related compartment of yeast. Eur. J. Biochem. 218:565–574.
Friedlander, R., Jarosch, E., Urban, J., et al. (2000). A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat. Cell Biol. 2:379–384.
Frohlich, K.U., Fries, H.W., Rudiger, M., et al. (1991). Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression. J. Cell Biol. 114:443–453.
Funakoshi, M., Sasaki, T., Nishimoto, T. et al. (2002). Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. Proc. Natl. Acad. Sci. USA. 99:745–750.
Gardner, R.G., Swarbrick, G.M., Bays, N.W., et al. (2000). Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J. Cell Biol. 151:69–82.
Gauss, R., Jarosch, E., Sommer, T. et al. (2006a). A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat. Cell Biol. 8:849–854.
Gauss, R., Sommer, T., Jarosch, E. (2006b). The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 25:1827–1835.
Gnann, A., Riordan, J.R., Wolf, D.H. (2004). Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Mol. Biol. Cell 15:4125–4135.
Gross, E., Sevier, C.S., Heldman, N., et al. (2006). Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc. Natl. Acad. Sci. USA. 103: 299–304.
Hampton, R.Y., Gardner, R.G., Rine, J. (1996). Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol. Biol. Cell 7:2029–2044.
Hampton, R.Y. (2002). ER-associated degradation in protein quality control and cellular regulation. Curr. Opin. Cell Biol. 14:476–482.
Hampton, R.Y. (2003). IRE1: a role in UPREgulation of ER degradation. Dev. Cell 4:144–146.
Harris, S.L., Na, S., Zhu, X., et al. (1994). Dominant lethal mutations in the plasma membrane H(+)-ATPase gene of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA. 91:10531–10535.
Helenius, A., and Aebi, M. (2004). Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73:1019–1049.
Hiller, M.M., Finger, A., Schweiger, M., et al. (1996). ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273:1725–1728.
Hirao, K., Natsuka, Y., Tamura, T., et al. (2006). EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J. Biol. Chem. 281:9650–9658.
Hirsch, C., Misaghi, S., Blom, D., et al. (2004). Yeast N-glycanase distinguishes between native and non-native glycoproteins. EMBO Rep. 5:201–206.
Hirsch, C., Gauss, R., Sommer, T. (2006). Coping with stress: cellular relaxation techniques. Trends Cell Biol. 16:657–663.
Hitchcock, A.L., Krebber, H., Frietze, S., et al. (2001). The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol. Biol. Cell 12:3226–3241.
Hitt, R., and Wolf, D.H. (2004a). DER7, encoding alpha-glucosidase I is essential for degradation of malfolded glycoproteins of the endoplasmic reticulum. FEMS Yeast Res. 4:815–820.
Hitt, R., and Wolf, D.H. (2004b). Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins. FEMS Yeast Res. 4:721–729.
Hiyama, H., Yokoi, M., Masutani, C., et al. (1999). Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26 S proteasome. J. Biol. Chem. 274:28019–28025.
Hoppe, T. (2005). Multiubiquitylation by E4 enzymes: ‘one size’ doesn’t fit all. Trends Biochem. Sci. 30:183–187.
Hosokawa, N., Wada, I., Hasegawa, K., et al. (2001). A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep. 2:415–422.
Huyer, G., Longsworth, G.L., Mason, D.L., et al. (2004a). A striking quality control subcompartment in Saccharomyces cerevisiae: the endoplasmic reticulum-associated compartment. Mol. Biol. Cell 15:908–921.
Huyer, G., Piluek, W.F., Fansler, Z., et al. (2004b). Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J. Biol. Chem. 279:38369–38378.
Imai, Y., Soda, M., Inoue, H., et al. (2001). An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902.
Imai, Y., Soda, M., Hatakeyama, S., et al. (2002). CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol. Cell 10:55–67.
Jakob, C.A., Burda, P., Roth, J., et al. (1998). Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J. Cell Biol. 142:1223–1233.
Jakob, C.A., Bodmer, D., Spirig, U., et al. (2001). Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2:423–430.
Jarosch, E., Taxis, C., Volkwein, C., et al. (2002). Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat. Cell Biol. 4:134–139.
Kaganovich, D., Kopito, R., Frydman, J. (2008). Misfolded proteins partition between two distinct quality control compartments. Nature 454:1088–1095.
Kanehara, K., Kawaguchi, S., Ng D.T. (2007). The EDEM and Yos9p families of lectin-like ERAD factors. Semin. Cell Dev. Biol. 18:743–750.
Kikkert, M., Doolman, R., Dai, M., et al. (2004). Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J. Biol. Chem. 279:3525–3534.
Kim, I., Mi, K., Rao, H. (2004). Multiple interactions of rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol. Biol. Cell 15:3357–3365.
Kim, W., Spear, E.D., Ng, D.T. (2005). Yos9p detects and targets misfolded glycoproteins for ER-associated degradation. Mol. Cell 19:753–764.
Klionsky, D.J. (2007). Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell. Biol. 8:931–937.
Knop, M., Finger, A., Braun, T., et al. (1996). Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J. 15:753–763.
Koegl, M., Hoppe, T., Schlenker, S., et al. (1999). A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96:635–644.
Kolling, R., and Hollenberg, C.P. (1994). The ABC-transporter Ste6 accumulates in the plasma membrane in a ubiquitinated form in endocytosis mutants. EMBO J. 13:3261–3271.
Kopito, R.R. (1997). ER quality control: the cytoplasmic connection. Cell 88:427–430.
Kostova, Z., and Wolf, D.H. (2003). For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J. 22:2309–2317.
Kozutsumi, Y., Normington, K., Press, E., et al. (1989). Identification of immunoglobulin heavy chain binding protein as glucose-regulated protein 78 on the basis of amino acid sequence, immunological cross-reactivity, and functional activity. J. Cell Sci. Suppl. 11:115–137.
Krebs, M.P., Noorwez, S.M., Malhotra, R., et al. (2004). Quality control of integral membrane proteins. Trends Biochem. Sci. 29:648–655.
Kreft, S.G., Wang, L., Hochstrasser, M. (2006). Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J. Biol. Chem. 281:4646–4653.
Lenk, U., Yu, H., Walter, J., et al. (2002). A role for mammalian Ubc6 homologues in ER-associated protein degradation. J. Cell Sci. 115:3007–3014.
Levine, B., and Klionsky, D.J. (2004). Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6:463–477.
Lilley, B.N., and Ploegh, H.L. (2004). A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429:834–840.
Loayza, D., Tam, A., Schmidt, W.K., et al. (1998). Ste6p mutants defective in exit from the endoplasmic reticulum (ER) reveal aspects of an ER quality control pathway in Saccharomyces cerevisiae. Mol. Biol. Cell 9:2767–2784.
Madsen, L., Schulze, A., Seeger, M., et al. (2007). Ubiquitin domain proteins in disease. BMC Biochem. 8(Suppl 1): S1.
Mah, A.L., Perry, G., Smith, M.A., et al. (2000). Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J. Cell Biol. 151:847–862.
Mast, S.W., Diekman, K., Karaveg, K., et al. (2005). Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15:421–436.
Mazon, M.J., Eraso, P., Portillo, F. (2007). Efficient degradation of misfolded mutant Pma1 by endoplasmic reticulum-associated degradation requires Atg19 and the Cvt/autophagy pathway. Mol. Microbiol. 63:1069–1077.
McCracken, A.A., and Brodsky, J.L. (1996). Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J. Cell Biol. 132:291–298.
McCracken, A.A., and Brodsky, J.L. (2003). Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD). Bioessays 25:868–877.
McGrath, J.P., and Varshavsky, A. (1989). The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–404.
Meacham, G.C., Patterson, C., Zhang, W., et al. (2001). The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat. Cell Biol. 3:100–105.
Medicherla, B., Kostova, Z., Schaefer, A., et al. (2004). A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep. 5:692–697.
Metzger, M.B., Maurer, M.J., Dancy, B.M., et al. (2008). Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery. J. Biol. Chem. 283:32302–32316.
Meusser, B., Hirsch, C., Jarosch, E., et al. (2005). ERAD: the long road to destruction. Nat. Cell Biol. 7:766–772.
Meyer, H.H., Shorter, J.G., Seemann, J., et al. (2000). A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19:2181–2192.
Molinari, M., Calanca, V., Galli, C., et al. (2003). Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299:1397–1400.
Movsichoff, F., Castro, O.A., Parodi, A.J. (2005). Characterization of Schizosaccharomyces pombe ER alpha-mannosidase: a reevaluation of the role of the enzyme on ER-associated degradation. Mol. Biol. Cell 16:4714–4724.
Nadav, E., Shmueli, A., Barr, H., et al. (2003). A novel mammalian endoplasmic reticulum ubiquitin ligase homologous to the yeast Hrd1. Biochem. Biophys. Res. Commun. 303:91–97.
Nakamoto, R.K., Verjovski-Almeida, S., Allen, K.E., et al. (1998). Substitutions of aspartate 378 in the phosphorylation domain of the yeast PMA1 H + -ATPase disrupt protein folding and biogenesis. J. Biol. Chem. 273:7338–7344.
Nakatsukasa, K., Nishikawa, S., Hosokawa, N., et al. (2001). Mnl1p, an alpha-mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins. J. Biol. Chem. 276:8635–8638.
Nakatsukasa, K., and Brodsky, J.L. (2008). The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 9:861–870.
Nakatsukasa, K., Huyer, G., Michaelis, S., et al. (2008). Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132:101–112.
Neuber, O., Jarosch, E., Volkwein, C., et al. (2005). Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat. Cell Biol. 7:993–998.
Nishikawa, S.I., Fewell, S.W., Kato, Y., et al. T (2001). Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J. Cell Biol. 153:1061–1070
Nishitoh, H., Kadowaki, H., Nagai, A., et al. (2008). ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 22:1451–1464.
Nita-Lazar, M., and Lennarz, W.J. (2005). Pkc1p modifies CPY* degradation in the ERAD pathway. Biochem. Biophys. Res. Commun. 332:357–361.
Norgaard, P., Westphal, V., Tachibana, C., et al. (2001). Functional differences in yeast protein disulfide isomerases. J. Cell Biol. 152:553–562.
Normington, K., Kohno, K., Kozutsumi, Y., et al. (1989). S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP. Cell 57:1223–1236.
Oda, Y., Hosokawa, N., Wada, I., et al. (2003). EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299:1394–1397.
Omura, T., Kaneko, M., Okuma, Y., et al. (2006). A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. J. Neurochem. 99:1456–1469.
Park, S, Isaacson, R., Kim, H.T., et al. (2005). Ufd1 exhibits the AAA-ATPase fold with two distinct ubiquitin interaction sites. Structure 13:995–1005.
Pilon, M., Schekman, R., Romisch, K. (1997). Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J. 16:4540–4548.
Plemper, R.K., Bohmler, S., Bordallo, J., et al. (1997). Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388: 891–895.
Plemper, R.K., Egner, R., Kuchler, K., et al. (1998). Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome. J. Biol. Chem. 273: 32848–32856.
Plemper, R.K., Bordallo, J., Deak, P.M., et al. (1999). Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J. Cell Sci. 112 (Pt 22):4123–4134.
Plemper, R.K., and Wolf, D.H. (1999). Endoplasmic reticulum degradation. Reverse protein transport and its end in the proteasome. Mol. Biol. Rep. 26:125–130.
Rabinovich, E., Kerem, A., Frohlich, K.U., et al. (2002). AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell Biol. 22:626–634.
Rape, M., Hoppe, T., Gorr, I., et al. (2001). Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48 (UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107:667–677.
Ravid, T., Kreft, S.G., Hochstrasser, M. (2006). Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J. 25:533–543.
Richly, H., Rape, M., Braun, S., et al. (2005). A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120:73–84.
Romisch, K. (1999). Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane. J. Cell Sci. 112 (Pt 23):4185–4191.
Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8:519–529.
Rose, M.D., Misra, L.M., Vogel, J.P. (1989). KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene. Cell 57:1211–1221.
Rumpf, S., and Jentsch, S. (2006). Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. Mol. Cell 21:261–269.
Sai, X., Kawamura, Y., Kokame, K., et al. (2002). Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J. Biol. Chem. 277:12915–12920.
Saris, N., Holkeri, H., Craven, R.A., et al. (1997). The Hsp70 homologue Lhs1p is involved in a novel function of the yeast endoplasmic reticulum, refolding and stabilization of heat-denatured protein aggregates. J. Cell Biol. 137:813–824.
Sato, B.K., and Hampton, R.Y. (2006). Yeast Derlin Dfm1 interacts with Cdc48 and functions in ER homeostasis. Yeast 23:1053–1064.
Schuberth, C., Richly, H., Rumpf, S., et al. (2004). Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep. 5:818–824.
Schwieger, I., Lautz, K., Krause, E., et al. (2008). Derlin-1 and p97/valosin-containing protein mediate the endoplasmic reticulum-associated degradation of human V2 vasopressin receptors. Mol. Pharmacol. 73:697–708.
Scott, D.C., and Schekman, R. (2008). Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins. J. Cell Biol. 181:1095–1105.
Serrano, R., Kielland-Brandt, M.C., Fink, G.R. (1986). Yeast plasma membrane ATPase is essential for growth and has homology with (Na+, K+), K + - and Ca2+-ATPases. Nature 319:689–693.
Shamu, C.E., Cox, J.S., Walter, P. (1994). The unfolded-protein-response pathway in yeast. Trends Cell Biol. 4:56–60.
Shamu, C.E., and Walter, P. (1996). Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 15:3028–3039.
Sidrauski, C., Chapman, R., Walter, P. (1998). The unfolded protein response: an intracellular signalling pathway with many surprising features. Trends Cell Biol. 8:245–249.
Sitia, R., and Braakman, I. (2003). Quality control in the endoplasmic reticulum protein factory. Nature 426:891–894.
Sommer, T., and Jentsch, S. (1993). A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365:176–179.
Song, Y., Sata, J., Saito, A., et al. (2001). Effects of calnexin deletion in Saccharomyces cerevisiae on the secretion of glycosylated lysozymes. J. Biochem. 130:757–764.
Spear, E.D., and Ng, D.T. (2005). Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J. Cell Biol. 169:73–82.
Staub, O., and Rotin, D. (2006). Role of ubiquitylation in cellular membrane transport. Physiol. Rev. 86:669–707.
Supply, P., Wach, A., Thines-Sempoux, D., et al. (1993). Proliferation of intracellular structures upon overexpression of the PMA2 ATPase in Saccharomyces cerevisiae. J. Biol. Chem. 268:19744–19752.
Suzuki, T., Park, H., Hollingsworth, N.M., et al. (2000). PNG1, a yeast gene encoding a highly conserved peptide: N-glycanase. J. Cell Biol. 149:1039–1052.
Swanson, R., Locher, M., Hochstrasser, M. (2001). A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev. 15:2660–2674.
Szathmary, R., Bielmann, R., Nita-Lazar, M., et al. (2005). Yos9 protein is essential for degradation of misfolded glycoproteins and may function as lectin in ERAD. Mol. Cell 19:765–775.
Takeuchi, S. (2006). Molecular cloning, sequence, function and structural basis of human heart 150 kDa oxygen-regulated protein, an ER chaperone. Protein J. 25:517–528.
Taxis, C., Hitt, R., Park, S.H., et al. (2003). Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. J. Biol. Chem. 278:35903–35913.
Travers, K.J., Patil, C.K., Wodicka, L., et al. (2000). Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258.
Tsai, B., Ye, Y., Rapoport, T.A. (2002). Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat. Rev. Mol. Cell. Biol. 3:246–255.
Ushioda, R., Hoseki, J., Araki, K., et al. (2008). ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. Science 321:569–572.
Vashist, S., and Ng, D.T. (2004). Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J. Cell Biol. 165:41–52.
Wahlman, J., DeMartino, G.N., Skach, W.R., et al. (2007). Real-time fluorescence detection of ERAD substrate retrotranslocation in a mammalian in vitro system. Cell 129:943–955.
Wakabayashi-Nakao, K., Tamura, A., Furukawa, T., et al. (2009). Quality control of human ABCG2 protein in the endoplasmic reticulum: ubiquitination and proteasomal degradation. Adv. Drug Deliv. Rev. 61:66–72.
Walter, J., Urban, J., Volkwein, C., et al. (2001). Sec61p-independent degradation of the tail-anchored ER membrane protein Ubc6p. EMBO J. 20:3124–3131.
Wang, G., Sawai, N., Kotliarova, S., et al. (2000). Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum. Mol. Genet. 9:1795–1803.
Wang, L., Dong, H., Soroka, C.J., et al. (2008). Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology 48:1558–1569.
Wang, Q., and Chang, A. (1999). Eps1, a novel PDI-related protein involved in ER quality control in yeast. EMBO J. 18:5972–5982.
Ward, C.L., Omura, S., Kopito, R.R. (1995). Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83: 121–127.
Weihl, C.C., Dalal, S., Pestronk, A., et al. (2006). Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum. Mol. Genet. 15:189–199.
Werner, E.D., Brodsky, J.L., McCracken, A.A. (1996). Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc. Natl. Acad. Sci. USA. 93:13797–13801.
Wiertz, E.J., Tortorella, D., Bogyo, M., et al. (1996). Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384: 432–438.
Willer, M., Forte, G.M., Stirling, C.J. (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. 283:33883–33888.
Wright, R., Basson, M., D’Ari, L., et al. (1988). Increased amounts of HMG-CoA reductase induce “karmellae”: a proliferation of stacked membrane pairs surrounding the yeast nucleus. J. Cell Biol. 107:101–114.
Wu, J., and Kaufman, R.J. (2006). From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ. 13:374–384.
Yagishita, N., Yamasaki, S., Nishioka, K., et al. (2008). Synoviolin, protein folding and the maintenance of joint homeostasis. Nat. Clin. Pract. Rheumatol. 4:91–97.
Ye, Y., Meyer, H.H., Rapoport, T.A. (2001). The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414:652–656.
Ye, Y., Shibata, Y., Yun, C., et al. (2004). A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847.
Younger, J.M., Chen. L., Ren, H.Y., et al. (2006). Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126:571–582.
Acknowledgements
We apologize to those whose work we were unable to cite due to space constraints. N. C is supported by a grant from the Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Campagnolo, N., Ghislain, M. (2011). ER-associated Degradation and Its Involvement in Human Disease: Insights from Yeast. In: Vidal, C. (eds) Post-Translational Modifications in Health and Disease. Protein Reviews, vol 13. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6382-6_14
Download citation
DOI: https://doi.org/10.1007/978-1-4419-6382-6_14
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-6381-9
Online ISBN: 978-1-4419-6382-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)