Lipid bilayer thinning near a ubiquitin ligase selects ER membrane proteins for degradation.

Misfolded or unassembled membrane proteins in the endoplasmic reticulum (ER) are polyubiquitinated, translocated into the cytosol, and degraded by the proteasome, a poorly understood process that is conserved in all eukaryotes. Here, we use S. cerevisiae to elucidate how ER membrane proteins are selected for degradation. We show that hydrophilic residues in a trans-membrane (TM) segment cause the TM to partition into a thinned membrane region next to the ubiquitin ligase Hrd1, which then leads to substrate polyubiquitination and degradation. In the case of single-pass membrane proteins, the Hrd1-associated Der1 protein contributes to partitioning and degradation. In contrast, multi-pass proteins require Hrd1 to function on its own. Our results provide a general mechanism by which ER membrane proteins are targeted for degradation.