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Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation
Di, Xiao-Jing Wang, Ya-Juan Han, Dong-Yun Fu, Yan-Lin Duerfeldt, Adam S. Blagg, Brian S. J. Mu, Ting-Wei
Di, Xiao-Jing
Wang, Ya-Juan
Han, Dong-Yun
Fu, Yan-Lin
Duerfeldt, Adam S.
Blagg, Brian S. J.
Mu, Ting-Wei
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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.
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.
Date
2016-03-04
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American Society for Biochemistry and Molecular Biology
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Keywords
Cys-loop receptor, Endoplasmic reticulum-associated protein degradation (ERAD), Epilepsy, γ-aminobutyric acid (GABA), Protein misfolding, Proteostasis, Grp94, Hrd1, OS-9, VCP
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.