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

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Abstract

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 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 hair cell defects in 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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All data generated or analyzed during this study are included in the manuscript and supporting files. Source Data files have been provided.

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Ge Gao

Institutes of Brain Science, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Shuyu Guo

Institutes of Brain Science, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Quan Zhang

Institutes of Brain Science, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Hefei Zhang

Institutes of Brain Science, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Cuizhen Zhang

Institutes of Brain Science, Fudan University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Gang Peng

Institute of Brain Science, Fudan University, Shanghai, China

For correspondence
gangpeng@fudan.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6625-5426

Funding

National Key Research and Development Program of China (2018YFA0801000)

Gang Peng

National Natural Science Foundation of China (31571067)

Gang Peng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The animal use protocols were approved by the Fudan University Shanghai Medical College Institution Animal Care and Use Committee (130227-092, 150119-088 and 190221-147). All animals were handled in accordance with the Fudan University Regulations on Animal Experiments.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.