Abstract
Quality control of protein folding inside the endoplasmic reticulum (ER) includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called ER-associated protein degradation, or simply ERAD. Once selected for ERAD, substrates will be transported (back) into the cytosol, a step called retrotranslocation. Although still ill defined, retrotranslocation likely involves a protein conducting channel that is in part formed by specific membrane-embedded E3 ubiquitin ligases. Early during retrotranslocation, reversible self-ubiquitination of these ligases is thought to aid in initiation of substrate transfer across the membrane. Once being at least partially exposed to the cytosol, substrates will become ubiquitinated on the cytosolic side of the ER membrane by the same E3 ubiquitin ligases. Ubiquitin on substrates was originally thought to be a permanent modification that (1) promotes late steps of retrotranslocation by recruiting the energy-providing ATPase Cdc48p/p97 via binding to its associated adaptor proteins and that (2) serves to target substrates to the proteasome. Recently it became evident, however, that the poly-ubiquitin chains (PUCs) on ERAD substrates are often subject to extensive remodeling, or processing, at several stages during ERAD. This review recapitulates the current knowledge and recent findings about PUC processing on ERAD substrates and ubiquitination of ERAD machinery components and discusses their functional consequences.
Highlights
Includes chaperone-mediated assistance in folding and the selective targeting of terminally misfolded species to a pathway called endoplasmic reticulum (ER)-associated protein degradation, or ERAD
CD4 mutants could only be explained by kinetic modeling incorporating deubiquitinating enzymes (DUBs) activity. This was supported by subsequent in vitro and in vivo experiments using DUB inhibitors [37]. Based on their observations the authors proposed a model where frequent ubiquitination is occurring on many cellular substrates, in particular on those that are restricted to the membrane and are in constant vicinity to membrane-embedded E3 ligases, such as those involved in ERAD
The authors of this study proposed that the DUB would act downstream of p97-mediated retrotranslocation and would trim the poly-ubiquitin chains (PUCs) on substrates if necessary to maintain an optimal signal for targeting to the proteasome, thereby streamlining protein retrotranslocation with their recognition by the proteasome (Figure 3B) [57]
Summary
Up to 30% of all proteins in the eukaryotic cell are targeted to the secretory pathway. The initial translocation across or insertion into the membrane of the endoplasmic reticulum (ER) is mediated by the protein conducting Sec61-channel or “translocon”. It was thought that ubiquitination of ERAD substrates serves exclusively as a tag for ultimate recognition by the proteasome. As it will be discussed in this review, accumulating evidence shows that ubiquination has various additional roles for ERAD. DUBs remove single or multiple ubiquitins from polyubiquitin chains (PUCs), implying that PUCs on substrates are processed prior to their removal upon protein degradation by the proteasome. Ubiquitin appears to be important for ERAD by regulating the composition or conformation of machinery components thereby controlling ERAD efficiency and substrate retrotranslocation
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