1. Academic Validation
  2. TMUB1 is an endoplasmic reticulum-resident escortase that promotes the p97-mediated extraction of membrane proteins for degradation

TMUB1 is an endoplasmic reticulum-resident escortase that promotes the p97-mediated extraction of membrane proteins for degradation

  • Mol Cell. 2022 Sep 15;82(18):3453-3467.e14. doi: 10.1016/j.molcel.2022.07.006.
Linhan Wang 1 Jiqiang Li 1 Qingchen Wang 2 Man-Xi Ge 1 Jia Ji 1 Di Liu 1 Zhiyuan Wang 1 Yang Cao 3 Yaoyang Zhang 1 Zai-Rong Zhang 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 College of Life Sciences, Sichuan University, Chengdu, China.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: zrzhang@sioc.ac.cn.
Abstract

Membrane protein clients of endoplasmic reticulum (ER)-associated degradation must be retrotranslocated from the ER membrane by the AAA-ATPase p97 for proteasomal degradation. Before direct engagement with p97, client transmembrane domains (TMDs) that have partially or fully crossed the membrane must be constantly shielded to avoid non-native interactions. How client TMDs are seamlessly escorted from the membrane to p97 is unknown. Here, we identified ER-anchored TMUB1 as a TMD-specific escortase. TMUB1 interacts with the TMD of clients within the membrane and holds ∼10-14 residues of a hydrophobic sequence that is exposed out of membrane, using its transmembrane and cytosolic regions, respectively. The ubiquitin-like domain of TMUB1 recruits p97, which can pull client TMDs from bound TMUB1 into the cytosol. The disruption of TMUB1 escortase activity impairs retrotranslocation and stabilizes retrotranslocating intermediates of client proteins within the ER membrane. Thus, TMUB1 promotes TMD segregation by safeguarding the TMD movement from the membrane to p97.

Keywords

ERAD; TMUB1; endoplasmic-reticulum-associated degradation; escortase; membrane protein extraction; membrane protein quality control; p97/VCP; protein degradation; retrotranslocation.

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