Mechanisms of substrate processing during ER-associated protein degradation

Maintaining proteome integrity is essential for long-term viability of all organisms and is overseen by intrinsic quality control mechanisms. The secretory pathway of eukaryotes poses a challenge for such quality assurance as proteins destined for secretion enter the endoplasmic reticulum (ER) and become spatially segregated from the cytosolic machinery responsible for disposal of aberrant (misfolded or otherwise damaged) or superfluous polypeptides. The elegant solution provided by evolution is ER-membrane-bound ubiquitylation machinery that recognizes misfolded or surplus proteins or by-products of protein biosynthesis in the ER and delivers them to 26S proteasomes for degradation. ER-associated protein degradation (ERAD) collectively describes this specialized arm of protein quality control via the ubiquitin-proteasome system. But, instead of providing a single strategy to remove defective or unwanted proteins, ERAD represents a collection of independent processes that exhibit distinct yet overlapping selectivity for a wide range of substrates. Not surprisingly, ER-membrane-embedded ubiquitin ligases (ER-E3s) act as central hubs for each of these separate ERAD disposal routes. In these processes, ER-E3s cooperate with a plethora of specialized factors, coordinating recognition, transport and ubiquitylation of undesirable secretory, membrane and cytoplasmic proteins. In this Review, we focus on substrate processing during ERAD, highlighting common threads as well as differences between the many routes via ERAD. Endoplasmic reticulum-associated protein degradation (ERAD) enables removal of aberrant or surplus proteins from the ER. ERAD represents a collection of independent processes exhibiting distinct yet overlapping selectivity for a wide range of substrates, enabling efficient quality control of membrane and secretory proteins.

Automated summary

Maintaining the integrity of the proteome is crucial for the survival of organisms. The secretory pathway of eukaryotes poses challenges for quality control, but the evolution has developed an elegant solution called ERAD through the ER-membrane-bound ubiquitylation machinery. ERAD is a specialized arm of protein quality control that ensures the efficient removal of aberrant or surplus proteins from the ER.