![]() This includes initial phases of ERAD where proteins are triaged for degradation and subsequent phases such as protein retrotranslocation across the ER membrane. Moreover, it appears that PUCs can be processed during ERAD at several stages. 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. This is mainly linked to the findings that deubiquitinating enzymes (DUBs) are required for ERAD. However, as it will be discussed in this review, accumulating evidence shows that ubiquination has various additional roles for ERAD. Initially it was thought that ubiquitination of ERAD substrates serves exclusively as a tag for ultimate recognition by the proteasome. ĭuring ERAD, misfolded proteins are retrotranslocated back to the cytosol where they will undergo ubiquitination. ![]() The pathway is conserved among eukaryotes and has been named ER-associated (protein) degradation, or simply ERAD. A major cellular pathway is dedicated to remove terminally misfolded proteins from the lumen or the membrane of the ER and targets them for regulated degradation. Folding, however, is still inefficient and many proteins fail to acquire their native three-dimensional structure. Consequently, proteins fold post-translocationally inside the ER, a process that is aided and controlled by a battery of chaperones. It has only a narrow pore and requires that proteins cross the membrane in an unfolded state. The initial translocation across or insertion into the membrane of the endoplasmic reticulum (ER) is mediated by the protein conducting Sec61-channel or “translocon”. Up to 30% of all proteins in the eukaryotic cell are targeted to the secretory pathway. 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. 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. 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. 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. Early during retrotranslocation, reversible self-ubiquitination of these ligases is thought to aid in initiation of substrate transfer across the membrane. Although still ill defined, retrotranslocation likely involves a protein conducting channel that is in part formed by specific membrane-embedded E3 ubiquitin ligases. Once selected for ERAD, substrates will be transported (back) into the cytosol, a step called retrotranslocation. ![]() 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. ![]()
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