Grp94 protein delivers γ-aminobutyric acid type A (GABAA) receptors to Hrd1 protein-mediated endoplasmic reticulumassociated degradation

Xiao Jing Di, Ya Juan Wang, Dong Yun Han, Yan Lin Fu, Adam S. Duerfeldt, Brian S.J. Blagg, Ting Wei Mu

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 forGABAA 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.

Original languageEnglish (US)
Pages (from-to)9526-9539
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number18
DOIs
StatePublished - Apr 29 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Research Startup Fund from Case Western Reserve University School of Medicine (to T. W. M.), Epilepsy Foundation of America Grant 225243 (to T. W. M.), Clinical Translational Science Collaborative of Cleveland (CTSA) National Institutes of Health Grant UL1RR024989 from the NCRR and National Center for Advancing Translational Sciences (to T. W. M.), and National Institutes of Health Grants T32 HL007567 (to Y. J. W.) and CA109265 from NCI (to B. S. J. B.).

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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