Ubiquitin-dependent protein degradation at the endoplasmic reticulum and nuclear envelope.

Numerous nascent proteins undergo folding and maturation within the luminal and membrane compartments of the endoplasmic reticulum (ER). Despite the presence of various factors in the ER that promote protein folding, many proteins fail to properly fold and assemble and are subsequently degraded. Regulatory proteins in the ER also undergo degradation in a way that is responsive to stimuli or the changing needs of the cell. As in most cellular compartments, the ubiquitin-proteasome system (UPS) is responsible for the majority of the degradation at the ER-in a process termed ER-associated degradation (ERAD). Autophagic processes utilizing ubiquitin-like protein-conjugating systems also play roles in protein degradation at the ER. The ER is continuous with the nuclear envelope (NE), which consists of the outer nuclear membrane (ONM) and inner nuclear membrane (INM). While ERAD is known also to occur at the NE, only some of the ERAD ubiquitin-ligation pathways function at the INM. Protein degradation machineries in the ER/NE target a wide variety of substrates in multiple cellular compartments, including the cytoplasm, nucleoplasm, ER lumen, ER membrane, and the NE. Here, we review the protein degradation machineries of the ER and NE and the underlying mechanisms dictating recognition and processing of substrates by these machineries.