Mechanisms of transmembrane domain recognition during endoplasmic reticulum quality control

Misfolded proteins can be toxic to cells, and their accumulation is a hallmark of diseases such as neurodegeneration. Normally, protein homeostasis is maintained by quality control processes that eliminate misfolded proteins. In the endoplasmic reticulum (ER), misfolded proteins are eliminated through endoplasmic reticulum–associated degradation (ERAD). This process is mediated by ubiquitin ligase complexes that recognize substrates in the membrane and lumen of the ER and retrotranslocate them to the cytosol to mediate their ubiquitination for subsequent degradation by the proteasome. While the recognition of luminal substrates is well understood, how ERAD complexes specifically identify and select aberrant membrane proteins remains poorly defined. Here, we review examples of intramembrane substrate recognition during ERAD and discuss the principles involved.