Publication Date:
2022-05-25
Description:
© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Cell Reports 25 (2018): 1281–1291, doi:10.1016/j.celrep.2018.10.005.
Description:
Morphogenesis and mechanoelectrical transduction
of the hair cell mechanoreceptor depend on the correct
assembly of Usher syndrome (USH) proteins
into highly organized macromolecular complexes.
Defects in these proteins lead to deafness and
vestibular areflexia in USH patients. Mutations in a
non-USH protein, glutaredoxin domain-containing
cysteine-rich 1 (GRXCR1), cause non-syndromic
sensorineural deafness. To understand the deglutathionylating
enzyme function of GRXCR1 in deafness,
we generated two grxcr1 zebrafish mutant
alleles. We found that hair bundles are thinner in
homozygous grxcr1 mutants, similar to the USH1
mutants ush1c (Harmonin) and ush1ga (Sans).
In vitro assays showed that glutathionylation promotes
the interaction between Ush1c and Ush1ga
and that Grxcr1 regulates mechanoreceptor development
by preventing physical interaction between
these proteins without affecting the assembly
of another USH1 protein complex, the Ush1c-
Cadherin23-Myosin7aa tripartite complex. By elucidating
the molecular mechanism through which
Grxcr1 functions, we also identify a mechanism that
dynamically regulates the formation of Usher protein
complexes.
Description:
This work was supported by grants from the NIH (DC004186, OD011195, and HD22486).
Keywords:
Grxcr1
;
Usher syndrome
;
Hair cell
;
Stereocilia
;
Glutathionylation
;
Harmonin
;
Sans
Repository Name:
Woods Hole Open Access Server
Type:
Article
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