title: Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L.
abstract: 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 HRD1, an integral membrane ubiquitin ligase that ubiquitinates ERAD substrates, forms a large assembly in the ER membrane including SEL1L, 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 SEL1L is an unstable protein, which is restored by the association with HRD1. Here we report that the inherently unstable nature of the human SEL1L protein lies in its transmembrane domain, and that association of HRD1 with the SEL1L transmembrane domain restored its stability. On the other hand, we found that the SEL1L luminal domain escaped degradation, and inhibited the degradation of misfolded α1 -antitrypsin variant null Hong Kong by retaining the misfolded cargo in the ER. Overexpression of HRD1 inhibited the degradation of unfolded secretory cargo, which was restored by the interaction of HRD1 with the SEL1L transmembrane domain. Hence, we propose that SEL1L critically regulates HRD1-mediated disposal of misfolded cargo through its short membrane spanning stretch.
authors.affiliation: Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Hosokawa
authors.affiliation: Department of Cell Sciences, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Wada
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D011506:Proteins; C117384:SEL1L protein, human; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ER-associated degradation; HRD1 ubiquitin ligase complex; SEL1L protein; endoplasmic reticulum; membrane protein