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Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles

Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was un...

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Autores principales: Gao, Ge, Guo, Shuyu, Zhang, Quan, Zhang, Hefei, Zhang, Cuizhen, Peng, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714970/
https://www.ncbi.nlm.nih.gov/pubmed/36317962
http://dx.doi.org/10.7554/eLife.80865
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author Gao, Ge
Guo, Shuyu
Zhang, Quan
Zhang, Hefei
Zhang, Cuizhen
Peng, Gang
author_facet Gao, Ge
Guo, Shuyu
Zhang, Quan
Zhang, Hefei
Zhang, Cuizhen
Peng, Gang
author_sort Gao, Ge
collection PubMed
description Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.
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spelling pubmed-97149702022-12-02 Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles Gao, Ge Guo, Shuyu Zhang, Quan Zhang, Hefei Zhang, Cuizhen Peng, Gang eLife Cell Biology Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing. eLife Sciences Publications, Ltd 2022-11-01 /pmc/articles/PMC9714970/ /pubmed/36317962 http://dx.doi.org/10.7554/eLife.80865 Text en © 2022, Gao et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Gao, Ge
Guo, Shuyu
Zhang, Quan
Zhang, Hefei
Zhang, Cuizhen
Peng, Gang
Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title_full Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title_fullStr Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title_full_unstemmed Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title_short Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
title_sort kiaa1024l/minar2 is essential for hearing by regulating cholesterol distribution in hair bundles
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714970/
https://www.ncbi.nlm.nih.gov/pubmed/36317962
http://dx.doi.org/10.7554/eLife.80865
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