Endoplasmic reticulum degradation. Reverse protein transport and its end in the proteasome.
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, Derl, Der3/Hrd1, and Hrd3 are specifically involved in the retrograde transport processes.
Plemper
R K
RK
Universität Stuttgart, Institut für Biochemie, Germany.
Wolf
D H
DH
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D002268:Carboxypeptidases / Q000378:metabolism; D043402:Cathepsin A; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins
D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D002268:Carboxypeptidases; D043402:Cathepsin A; C499283:PRC1 protein, S cerevisiae; C022633:serine carboxypeptidase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases