Abstract
Degradation of misfolded or unassembled proteins of the secretory pathway is an essential function of the quality control system of the Endoplasmic Reticulum (ER). Using yeast as a model organism we show that a mutated and therefore misfolded soluble lumenal protein carboxypeptidase yscY (CPY*), and a polytopic membrane protein, the ATP-binding cassette transporter Pdr5 (Pdr5*), are retrograde transported out of the ER and degraded via the cytoplasmic ubiquitin-proteasome system. Retrograde transport depends on an intact Sec61 translocon. Complete import of CPY* into the lumen of the ER requests a new targeting mechanism for retrograde transport of the malfolded enzyme through the Sec61 channel to occur. For soluble CPY*, but not for the polytopic membrane protein Pdr5* action of the ER-lumenal Hsp70 chaperone Kar2 is necessary to deliver the protein to the ubiquitin-proteasome machinery. Polyubiquitination of CPY* and Pdr5* by the ubiquitin conjugating enzymes Ubc6 and Ubc7 is crucial for degradation to occur. Also transport of CPY* out of the ER-lumen depends on ubiquitination. Newly discovered proteins of the ER membrane, Der1, Der3/Hrd1, and Hrd3 are specifically involved in the retrograde transport processes.
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References
Rapoport TA, Jungnickel B & Kutay U (1996) Annu. Rev. Biochem. 65: 271–303
Gaut JR & Hendershot LM (1993) Curr. Opin. Cell Biol. 5: 589–595
Klausner RD & Sitia R (1990) Cell 62: 611–614
Bonifacino JS & Klausner RD (1994). In: Ciechanover AE & Schwartz AL (Eds) Modern Cell Biology, Cellular Proteolysis Systems (Vol. 15, pp. 137–160) Wiley-Liss., New York
Hieter P, Bassett Jr, DE & Valle D (1996) Nature Genet. 13: 253–255
Kopito RR (1997) Cell 88: 427–430
Sommer T & Wolf DH (1997) FASEB J. 11: 1227–1233
Wolf DH & Fink GR (1975) J. Bacteriol. 123: 1150–1156
Finger A, Knop M & Wolf DH (1993) Eur. J. Biochem. 218: 565–574
Egner R, Rosenthal FE, Kralli A, Sanglard D & Kuchler K (1998) Mol. Biol. Cell 9: 523–543
Hiller MM, Finger A, Schweiger M & Wolf DH (1996) Science 273: 1725–1728
Biederer T, Volkwein C & Sommer T (1997) Science 278: 1806–1809
Bordallo J, Plemper RK, Finger A & Wolf DH (1998) Mol. Biol. Cell 9: 209–222
Blobel G (1995) Cold Spring Harbor Symp. Quant. Biol. 60: 1–10
Plemper RK, Böhmler S, Bordallo J, Sommer T & Wolf DH (1997) Nature 388: 891–895
Dürr G, Strayle J, Plemper R, Elbs S, Klee S, Catty P, Wolf DH & Rudolph HK (1998) Mol. Biol. Cell 9: 1149–1162
Plemper RK, Deak PM, Otto RT & Wolf DH (1999) FEBS Lett. 443: 241–245
Knop M, Finger A, Braun T, Hellmuth K & Wolf DH (1996) EMBO J. 15: 753–763
Hampton RY, Gardner RG & Rine J (1996) Mol. Biol. Cell 7: 2029–2044
Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL & Riordan JR (1995) Cell 83: 129–135
Ward CL, Omura S & Kopito RR (1995) Cell 83: 121–127
Egner R, Mahé Y, Pandjaitan R & Kuchler K (1995) Mol. Cell Biol. 15: 5879–5887
Plemper RK, Egner R, Kuchler K & Wolf DH (1998) J. Biol. Chem. 273: 32848–32856
Hamman BD, Hendershot LM & Johnson AE (1998) Cell 92: 747–758
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Plemper, R.K., Wolf, D.H. Endoplasmic reticulum degradation. Reverse protein transport and its end in the proteasome. Mol Biol Rep 26, 125–130 (1999). https://doi.org/10.1023/A:1006913215484
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DOI: https://doi.org/10.1023/A:1006913215484