Multiubiquitination of TRPV4 reduces channel activity independent of surface localization.

Autor:	Aisenberg WH; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., McCray BA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Sullivan JM; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Diehl E; Department of Chemistry, Biochemistry Section, Johannes Gutenberg-Universität Mainz, Mainz, Germany., DeVine LR; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Alevy J; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Bagnell AM; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Carr P; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Donohue JK; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Goretzki B; Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-Universität, Jena, Germany; Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-Universität, Frankfurt am Main, Germany., Cole RN; Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-Universität, Jena, Germany., Hellmich UA; Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-Universität, Jena, Germany; Center for Biomolecular Magnetic Resonance (BMRZ), Goethe-Universität, Frankfurt am Main, Germany., Sumner CJ; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: csumner1@jhmi.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Apr; Vol. 298 (4), pp. 101826. Date of Electronic Publication: 2022 Mar 14.
DOI:	10.1016/j.jbc.2022.101826
Abstrakt:	Ubiquitin (Ub)-mediated regulation of plasmalemmal ion channel activity canonically occurs via stimulation of endocytosis. Whether ubiquitination can modulate channel activity by alternative mechanisms remains unknown. Here, we show that the transient receptor potential vanilloid 4 (TRPV4) cation channel is multiubiquitinated within its cytosolic N-terminal and C-terminal intrinsically disordered regions (IDRs). Mutagenizing select lysine residues to block ubiquitination of the N-terminal but not C-terminal IDR resulted in a marked elevation of TRPV4-mediated intracellular calcium influx, without increasing cell surface expression levels. Conversely, enhancing TRPV4 ubiquitination via expression of an E3 Ub ligase reduced TRPV4 channel activity but did not decrease plasma membrane abundance. These results demonstrate Ub-dependent regulation of TRPV4 channel function independent of effects on plasma membrane localization. Consistent with ubiquitination playing a key negative modulatory role of the channel, gain-of-function neuropathy-causing mutations in the TRPV4 gene led to reduced channel ubiquitination in both cellular and Drosophila models of TRPV4 neuropathy, whereas increasing mutant TRPV4 ubiquitination partially suppressed channel overactivity. Together, these data reveal a novel mechanism via which ubiquitination of an intracellular flexible IDR domain modulates ion channel function independently of endocytic trafficking and identify a contributory role for this pathway in the dysregulation of TRPV4 channel activity by neuropathy-causing mutations. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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