title: Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum.
abstract: Endoplasmic reticulum-associated degradation (ERAD) is an important system that eliminates misfolded proteins from the ER. Three derlins have been implicated in this process, but their precise function remains unknown. In this study, we report that although both derlin1 and derlin2 are capable of binding the ERAD-specific ubiquitin ligase HRD1, they associate with the HRD1-containing complex with different affinities. Accordingly, these derlins have nonredundant functions in ERAD with derlin2 being an essential functional partner for HRD1-mediated ERAD of SHH and NHK. We show that derlin2, but not derlin1 or derlin3, is required for ERAD of both glycosylated and nonglycosylated SHH, as well as NHK. Derlin2 appears to act at a post-targeting step for HRD1-dependent retro-translocation. Without derlin2, the assembly of HRD1 into a functional retro-translocation homo-oligomer proceeds normally, and substrate targeting to the HRD1 complex also occurs. However, the ERAD substrate SHH-C is largely trapped inside the ER lumen. These observations raise the possibility that derlin2 may regulate the movement of substrates through the HRD1-containing retro-translocon. Our study is the first to report that derlin2 functions with HRD1 in ERAD of certain substrates independent of their glycosylation status. The mammalian ERAD system may require multiple derlins that each functions with a distinct E3 partner to eliminate a specific subset of substrates. This is different from the model in Saccharomyces cerevisiae, in which Hrd1p alone is sufficient for retro-translocation.
authors.affiliation: From the Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan 35053, Republic of China.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.affiliation: From the Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan 35053, Republic of China.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Hsiao
authors.affiliation: From the Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan 35053, Republic of China.
authors.forename: Yue-Ru
authors.initials: YR
authors.lastname: Chu
authors.affiliation: the Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.affiliation: From the Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan 35053, Republic of China,; the Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40402, Republic of China. Electronic address: xchen@nhri.org.tw.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C513305:DERL2 protein, human; D053823:Hedgehog Proteins; D008565:Membrane Proteins; C509239:SHH protein, human; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Derlin; ER-associated Degradation; Endoplasmic Reticulum (ER); HRD1; Protein Degradation; Protein Translocation; Protein Turnover; Retro-translocation; Sonic Hedgehog