ZFIN ID: ZDB-PUB-181101-9
Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins
Blanco-Sánchez, B., Clément, A., Fierro, J., Stednitz, S., Phillips, J.B., Wegner, J., Panlilio, J.M., Peirce, J.L., Washbourne, P., Westerfield, M.
Date: 2018
Source: Cell Reports   25: 1281-1291.e4 (Journal)
Registered Authors: Blanco, Bernardo, Clément, Aurélie, Panlilio, Jennifer Martinez, Peirce, Judy, Phillips, Jennifer, Washbourne, Philip, Wegner, Jeremy, Westerfield, Monte
Keywords: Grxcr1, Harmonin, Sans, Usher syndrome, glutathionylation, hair cell, stereocilia
MeSH Terms:
  • Animals
  • Dogs
  • Glutathione/metabolism
  • Golgi Apparatus/metabolism
  • Hair Cells, Auditory/metabolism*
  • Madin Darby Canine Kidney Cells
  • Motor Activity
  • Mutation/genetics
  • Nerve Tissue Proteins/metabolism*
  • Protein Binding
  • Protein Transport
  • Stereocilia/metabolism
  • Substrate Specificity
  • Usher Syndromes/metabolism*
  • Zebrafish/metabolism*
  • Zebrafish Proteins/metabolism*
PubMed: 30380418 Full text @ Cell Rep.
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.