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Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD‐L
Author(s) -
Hosokawa Nobuko,
Wada Ikuo
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13564
Subject(s) - endoplasmic reticulum associated protein degradation , ubiquitin ligase , endoplasmic reticulum , transmembrane protein , microbiology and biotechnology , transmembrane domain , integral membrane protein , membrane protein , ubiquitin , stim1 , proteasome , cytoplasm , biology , ubiquitin protein ligases , unfolded protein response , biochemistry , membrane , receptor , gene
Misfolded proteins in the endoplasmic reticulum ( ER ) are transported to the cytoplasm for degradation by the ubiquitin–proteasome system, a process otherwise known as ER ‐associated degradation ( ERAD ). Mammalian HRD 1, an integral membrane ubiquitin ligase that ubiquitinates ERAD substrates, forms a large assembly in the ER membrane including SEL 1L, a single‐pass membrane protein, and additional components. The mechanism by which these molecules export misfolded proteins through the ER membrane remains unclear. Unlike Hrd3p, the homologue in Saccharomyces cerevisiae , human SEL 1L is an unstable protein, which is restored by the association with HRD 1. Here we report that the inherently unstable nature of the human SEL 1L protein lies in its transmembrane domain, and that association of HRD 1 with the SEL 1L transmembrane domain restored its stability. On the other hand, we found that the SEL 1L luminal domain escaped degradation, and inhibited the degradation of misfolded α 1 ‐antitrypsin variant null Hong Kong by retaining the misfolded cargo in the ER . Overexpression of HRD 1 inhibited the degradation of unfolded secretory cargo, which was restored by the interaction of HRD 1 with the SEL 1L transmembrane domain. Hence, we propose that SEL 1L critically regulates HRD 1‐mediated disposal of misfolded cargo through its short membrane spanning stretch.