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Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation
dc.contributor.author | Di, Xiao-Jing | |
dc.contributor.author | Wang, Ya-Juan | |
dc.contributor.author | Han, Dong-Yun | |
dc.contributor.author | Fu, Yan-Lin | |
dc.contributor.author | Duerfeldt, Adam S. | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.contributor.author | Mu, Ting-Wei | |
dc.date.accessioned | 2017-11-02T17:24:43Z | |
dc.date.available | 2017-11-02T17:24:43Z | |
dc.date.issued | 2016-03-04 | |
dc.identifier.citation | Di, X. J., Wang, Y. J., Han, D. Y., Fu, Y. L., Duerfeldt, A. S., Blagg, B. S., & Mu, T. W. (2016). Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. Journal of Biological Chemistry, 291(18), 9526-9539. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/25244 | |
dc.description | This research was originally published in the Journal of Biological Chemistry. Xiao-Jing Di, Ya-Juan Wang, Dong-Yun Han, Yan-Lin Fu, Adam S. Duerfeldt, Brian S. J. Blagg and Ting-Wei Mu.Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. Journal of Biological Chemistry. 2016; 291, 9526-9539. | en_US |
dc.description.abstract | Proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABAA receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABAA receptors. Here, using the α1 subunits of GABAA receptors as a model substrate, we demonstrated that Grp94, a metazoan-specific Hsp90 in the ER lumen, uses its middle domain to interact with the α1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded α1 subunits in a glycan-dependent manner. This delivers misfolded α1 subunits to the Hrd1-mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone α1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABAA receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions. | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology | en_US |
dc.rights | © The American Society for Biochemistry and Molecular Biology. | en_US |
dc.subject | Cys-loop receptor | en_US |
dc.subject | Endoplasmic reticulum-associated protein degradation (ERAD) | en_US |
dc.subject | Epilepsy | en_US |
dc.subject | γ-aminobutyric acid (GABA) | en_US |
dc.subject | Protein misfolding | en_US |
dc.subject | Proteostasis | en_US |
dc.subject | Grp94 | en_US |
dc.subject | Hrd1 | en_US |
dc.subject | OS-9 | en_US |
dc.subject | VCP | en_US |
dc.title | Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Blagg, Brian S. J. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1074/jbc.M115.705004 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-3130-9890 | |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |