Erad

ERAD, short for endoplasmic reticulum-associated degradation, is a cellular quality-control pathway that detects misfolded or unassembled proteins in the endoplasmic reticulum (ER) and targets them for degradation in the cytosol by the ubiquitin-proteasome system. It serves to maintain ER homeostasis and prevent the accumulation of defective proteins that could disrupt cellular function.

Substrates of ERAD are categorized by the location of their misfolding: ERAD-L for lumenal misfolded proteins, ERAD-M for membrane proteins with misfolded domains within the lipid bilayer, and ERAD-C for proteins with misfolding in their cytosolic domains. Recognition involves ER chaperones and lectins, such as BiP, OS-9, and XTP3-B, as well as membrane-associated adapters like SEL1L and DERLIN proteins that help identify and direct substrates toward the degradation machinery.

The degradation pathway proceeds through retrotranslocation (dislocation) of the substrate from the ER into the cytosol, a process that involves multimeric complexes including Derlin proteins and the HRD1–SEL1L E3 ubiquitin ligase complex. Ubiquitination is carried out by E2 enzymes (for example, UBE2J1), attaching ubiquitin chains to the substrate. The ATPase p97/VCP and its cofactors provide the pulling force to extract the ubiquitinated substrate into the cytosol, where it is deubiquitinated and delivered to the 26S proteasome for proteolysis. In many cases, the substrate is deglycosylated by NGLY1 during or after retrotranslocation.

ERAD is tightly linked to the unfolded protein response and ER‑stress signaling. It is essential for cellular proteostasis, and defects in ERAD components are implicated in diseases such as cystic fibrosis, alpha-1 antitrypsin deficiency, and various neurodegenerative disorders.