The Role of p97/Cdc48p in Endoplasmic Reticulum-Associated Degradation: From the Immune System to Yeast
Quality control mechanisms in the endoplasmic reticulum prevent deployment of aberrant or unwanted proteins to distal destinations and target them to degradation by a process known as endoplasmic reticulum-associated degradation, or ERAD. Attempts to characterize ERAD by identifying a specific component have revealed that the most general characteristic of ERAD is that the protein substrates are initially translocated to the ER and eventually eliminated in the cytosol by the ubiquitin-proteasome pathway. Hence, dislocation from the ER back to the cytosol is a hallmark in ERAD and p97/Cdc48p, a cytosolic AAA-ATPase that is essential for ERAD, appears to provide the driving force for this process. Moreover, unlike many ERAD components that participate in degradation of either lumenal or membrane substrates, p97/Cdc48p has a more general role in that it is required for ERAD of both types of substrates. Although p97/Cdc48p is not dedicated exclusively to ERAD, its ability to physically associate with ERAD substrates, with VIMP and with the E3 gp78 suggest that the p97/Cdc48Ufd1/Npl4 complex acts as a coordinator that maintains coupling between the different steps in ERAD.
Unable to display preview. Download preview PDF.
- Brodsky JL, Werner ED, Dubas ME, Goeckeler JL, Kruse KB, McCracken AA (1999) The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct. J Biol Chem 274:3453–3460CrossRefPubMedGoogle Scholar
- Huyer G, Piluek WF, Fansler Z, Kreft SG, Hochstrasser M, Brodsky JL, Michaelis S (2004) 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 279:38369–38378CrossRefPubMedGoogle Scholar