VCP – the missing link in protein degradation?

Abstract

Defective and abnormally folded proteins that are present within the lumen of the endoplasmic reticulum (ER) or associated with its membranes are rapidly degraded. This process is called ER-associated degradation (ERAD). ERAD is not solely a protein quality-control pathway, but it also involves the degradation of short-lived ER proteins such as fatty acid desaturase and HMG-CoA reductase. Curiously, ERAD does not take place within ER lumen but involves protein export to the cytosol, ubiquitination and degradation by 26S proteasomes. Until now, it was not clear how ER protein export is coupled to 26S proteasome targeting.This mystery is now at least partially solved. Several independent groups of researchers have shown that the missing link between the ER and the proteasome is a 97-kDa ATPase called VCP (valosin-containing protein, p97 or CDC48) [1.xThe AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Ye, Y et al. Nature. 2001; 414: 652–656Crossref | PubMed | Scopus (673)See all References, 2.xAAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Rabinovich, E et al. Mol. Cell. Biol. 2002; 22: 626–634Crossref | PubMed | Scopus (374)See all References, 3.xProtein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Jarosch, E et al. Nat. Cell Biol. 2002; 4: 134–139Crossref | PubMed | Scopus (358)See all References, 4.xRole of the ubiquitin-selective CDC48 (UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. Braun, S et al. EMBO J. 2002; 21: 615–621Crossref | PubMed | Scopus (243)See all References]. VCP is a ubiquituous enzyme, a member of the AAA family (‘ATPases with multiple cellular activities’), that is involved in a plethora of distinct functions such as membrane fusion, nuclear envelope reconstruction, post-mitotic Golgi reassembly and ubiquitin-dependent degradation. VCP forms a homohexamer that binds to several different ancillary proteins. VCP complex binds to polyubiquitin chains and has a chaperone activity that facilitates its ‘segregase’ function – the ability to untether ubiquitinated proteins from their binding partners. VCP in complex with Ufd1/Npl4 is therefore able to extract polyubiquitinated proteins associated with the translocon complex, removing them from ER to the cytoplasm. While some extracted proteins can be released into the cytosol, most of them are probably delivered to the 26S proteasome for degradation.These data establish VCP as a new component of the ubiquitin–proteasome system. It is not clear whether proteasome activity is also required for protein extraction from the ER. It is tempting to speculate that ERAD might be mediated by a macromolecular assembly involving direct interactions between the translocon, VCP, 26S proteasome and, possibly, specific ubiquitinating enzymes. Taking into account the importance of ERAD in various pathological processes, the detailed elucidation of its mechanisms could be of great practical value.