The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation

Abstract

The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.

Myeloid-derived growth factor is a resident endoplasmic reticulum protein

“…Finally, a global proteomic survey of ubiquitination sites identified modification of K137 of C19orf10 in myeloma cells treated with proteasome inhibitor (29). Collectively, these findings suggest that MYDGF may help in one or more of the steps that deliver proteins from the ER to the proteasome in ERAD (30,31).…”

“…30 software. An intensity threshold was first selected to define a mask of signal for both the 488 and 647 channels that was applied to each 0.3 µm slice of a confocal Z-series (21-41 eosinophils in the image plane).…”

Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes

“…The principles underlying ERAD involve recognition of misfolded proteins, targeting such proteins to the ERAD complex, retrotranslocation across the ER membrane, ubiquitylation of target proteins, extraction of ubiquitylated target proteins from the cytosolic face of the ER membrane, and degradation by 26S proteasomes. 128 The two core molecules of the ERAD machinery are the partner proteins HRD1 and SEL1/HRD3, which are conserved even in yeast. 129 The polytopic HRD1 membrane protein functions in both retrotranslocation and as an E3 ubiquitin ligase, whereas the single membrane–spanning SEL1 physically associates with HRD1 and is required for HRD1 protein stability, while also helping to present ERAD substrates to HRD1; many other ancillary proteins interact with the core complex, and these topics are reviewed in detail elsewhere.…”

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

“…Mammals have developed evolutionary‐conserved and internal quality control mechanisms at the ER, by which newly synthesized proteins are ‘proofread’, so that only the properly folded proteins can exit from the ER and be destined to the secretory pathway . The best characterized of these quality control mechanisms is the ER‐associated degradation (ERAD) pathway, a process by which folding of proteins is continuously monitored and misfolded polypeptides are dislocated from the ER to the cytosol to be degraded by the 26S proteasome . However, the role of additional quality control mechanisms is increasingly emerging, as not all misfolded ER clients are eligible for ERAD, and thus must be cleared from the ER through other alternative, ERAD‐independent processes.…”