2026/06/30 by Devanshi Agarwal, Kristina Solorio-Kirpichyan, Eric M. Jordahl +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Cellular transport and secretion #Endoplasmic Reticulum Stress and Disease #Lipid Membrane Structure and Behavior
paper · doi:10.1021/acs.chemrev.5c00780
openalex publication_date 2026/06/30 · openalex created_date 2026/07/01 · openalex updated_date 2026/07/23
Integral membrane proteins face unique folding challenges in the endoplasmic reticulum (ER) due to their hydrophobic transmembrane domains and complex topologies. Membrane protein misfolding disrupts ER homeostasis, contributing to diseases such as neurodegeneration, metabolic disorders, cystic fibrosis, and cancers. ER-associated degradation (ERAD) is a protein quality control pathway that detects, ubiquitinates, and retrotranslocates terminally misfolded proteins for proteasomal degradation in the cytosol. Recognition of membrane substrates involves multiple determinants, including topological lesions, exposed hydrophobic patches, and sequence-specific degrons. Recent advances in cryo-EM, functional genomics, and biochemical reconstitution studies have revealed new insights into the mechanistic actions of ERAD. This review addresses the current understanding of ERAD machinery dedicated to targeting misfolded membrane proteins, highlights emerging mechanistic models, and discusses how ERAD drives pathology. Understanding these principles will inform strategies for targeted manipulation of ER membrane protein quality control in health and disease.