SEL1L–HRD1-mediated ERAD in mammals

Abstract

Endoplasmic reticulum-associated degradation (ERAD) is a critical quality control mechanism responsible for eliminating misfolded or unassembled proteins. It maintains endoplasmic reticulum homeostasis, ensures a proper folding environment and regulates substrate protein levels. Following its discovery in the late 1980s and early 1990s, research on ERAD in mammals—particularly that mediated by the conserved protein complex comprising suppressor/enhancer of Lin-12-like protein 1-like (SEL1L) and HMG-CoA reductase degradation protein 1 (HRD1)—has advanced substantially over the past decade. SEL1L–HRD1-mediated ERAD is now recognized as a fundamental process in mammals that governs various physiological functions largely in a substrate-specific manner. In humans, mutations in this complex have been causally linked to ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) and ENDI-agammaglobulinaemia. This Review highlights the SEL1L–HRD1-mediated ERAD pathway, exploring its machinery, molecular mechanism and physiological relevance and potential therapeutic strategies targeting this system. This Review discusses emerging insights into SEL1L–HRD1-mediated endoplasmic reticulum-associated degradation, including the underlying molecular mechanisms, physiological relevance for human disease and potential therapeutic opportunities.