Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension

Brett A. McCray (), Erika Diehl, Jeremy M. Sullivan, William H. Aisenberg, Nicholas W. Zaccor, Alexander R. Lau, Dominick J. Rich, Benedikt Goretzki, Ute A. Hellmich, Thomas E. Lloyd and Charlotte J. Sumner ()
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Brett A. McCray: Johns Hopkins University School of Medicine
Erika Diehl: Biochemistry Section, Johannes Gutenberg-Universität Mainz
Jeremy M. Sullivan: Johns Hopkins University School of Medicine
William H. Aisenberg: Johns Hopkins University School of Medicine
Nicholas W. Zaccor: Johns Hopkins University School of Medicine
Alexander R. Lau: Johns Hopkins University School of Medicine
Dominick J. Rich: Johns Hopkins University School of Medicine
Benedikt Goretzki: Biochemistry Section, Johannes Gutenberg-Universität Mainz
Ute A. Hellmich: Biochemistry Section, Johannes Gutenberg-Universität Mainz
Thomas E. Lloyd: Johns Hopkins University School of Medicine
Charlotte J. Sumner: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of TRPV4 cause distinct, tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to the intracellular N-terminal domain whereas skeletal dysplasia mutations are in multiple domains. Using an unbiased screen, we identified the cytoskeletal remodeling GTPase RhoA as a TRPV4 interactor. TRPV4-RhoA binding occurs via the TRPV4 N-terminal domain, resulting in suppression of TRPV4 channel activity, inhibition of RhoA activation, and extension of neurites in vitro. Neuropathy but not skeletal dysplasia mutations disrupt TRPV4-RhoA binding and cytoskeletal outgrowth. However, inhibition of RhoA restores neurite length in vitro and in a fly model of TRPV4 neuropathy. Together these results identify RhoA as a critical mediator of TRPV4-induced cell structure changes and suggest that disruption of TRPV4-RhoA binding may contribute to tissue-specific toxicity of TRPV4 neuropathy mutations.

Date: 2021
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DOI: 10.1038/s41467-021-21699-y

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