Title:Roles of Ubiquitin in Endoplasmic Reticulum-Associated Protein Degradation (ERAD)
Volume: 13
Issue: 5
Author(s): Veit Goder
Affiliation:
Keywords:
ubiquitin, ERAD, retrotranslocation, Cdc48, p97, proteasome, E3 ubiquitin ligase.
Abstract: In the secretory pathway, quality control for the correct folding of proteins is largely occurring in the endoplasmic
reticulum (ER), at the earliest possible stage and in an environment where early folding intermediates mix with
terminally misfolded species. An elaborate cellular mechanism aims at dividing the former from the latter and promotes
the selective transport of misfolded species back into the cytosol, a step called retrotranslocation. During retrotranslocation
proteins will become ubiquitinated on the cytosolic side of the ER membrane by dedicated machineries and will be
targeted to the proteasome for degradation. The entire process, from protein recognition to final degradation, has been
named ER-associated protein degradation, or simply ERAD. Ubiquitin has well known functions in aiding late steps of
substrate retrotranslocation and in targeting substrates to the proteasome. Recent results show that several cytosolic machineries
allow ubiquitinated substrates to undergo extensive remodeling, or processing, on their poly-ubiquitin chains
(PUCs). Although still ill-defined, PUC processing might have a unique function for ERAD in that it might provide a
mechanism to generate optimal PUCs for recognition by proteasomal ubiquitin receptors. Ubiquitination might also have a
previously unanticipated role in quality control of ER membrane proteins. This review recapitulates the current knowledge
and recent findings about ERAD-specific roles of ubiquitin.
