TY  - JOUR
A1  - Aisenberg, William H.
A1  - McCray, Brett A.
A1  - Sullivan, Jeremy M.
A1  - Diehl, Erika
A1  - DeVine, Lauren R.
A1  - Alevy, Jonathan
A1  - Bagnell, Anna M.
A1  - Carr, Patrice
A1  - Donohue, Jack K.
A1  - Goretzki, Benedikt
A1  - Cole, Robert N.
A1  - Hellmich, Ute
A1  - Sumner, Charlotte J.
T1  - Multiubiquitination of TRPV4 reduces channel activity independent of surface localization
T2  - Journal of biological chemistry
N2  - 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.
KW  - TRPV4
KW  - ion channel
KW  - ubiquitination
KW  - plasma membrane
KW  - Charcot–Marie–Tooth disease
KW  - channel activation
KW  - NEDD4
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78599
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-785998
SN  - 0021-9258
VL  - 298
IS  - 4, art. 101826
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -