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LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility

Radial spokes (RS) are T-shaped multiprotein complexes on the axonemal microtubules. Repeated RS1, RS2, and RS3 couple the central pair to modulate ciliary and flagellar motility. Despite the cell type specificity of RS3 substructures, their molecular components remain largely unknown. Here, we repo...

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Autores principales: Hwang, Jae Yeon, Chai, Pengxin, Nawaz, Shoaib, Choi, Jungmin, Lopez-Giraldez, Francesc, Hussain, Shabir, Bilguvar, Kaya, Mane, Shrikant, Lifton, Richard P., Ahmad, Wasim, Zhang, Kai, Chung, Jean-Ju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980178/
https://www.ncbi.nlm.nih.gov/pubmed/36865175
http://dx.doi.org/10.1101/2023.02.25.530050
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author Hwang, Jae Yeon
Chai, Pengxin
Nawaz, Shoaib
Choi, Jungmin
Lopez-Giraldez, Francesc
Hussain, Shabir
Bilguvar, Kaya
Mane, Shrikant
Lifton, Richard P.
Ahmad, Wasim
Zhang, Kai
Chung, Jean-Ju
author_facet Hwang, Jae Yeon
Chai, Pengxin
Nawaz, Shoaib
Choi, Jungmin
Lopez-Giraldez, Francesc
Hussain, Shabir
Bilguvar, Kaya
Mane, Shrikant
Lifton, Richard P.
Ahmad, Wasim
Zhang, Kai
Chung, Jean-Ju
author_sort Hwang, Jae Yeon
collection PubMed
description Radial spokes (RS) are T-shaped multiprotein complexes on the axonemal microtubules. Repeated RS1, RS2, and RS3 couple the central pair to modulate ciliary and flagellar motility. Despite the cell type specificity of RS3 substructures, their molecular components remain largely unknown. Here, we report that a leucine-rich repeat-containing protein, LRRC23, is an RS3 head component essential for its head assembly and flagellar motility in mammalian spermatozoa. From infertile male patients with defective sperm motility, we identified a splice site variant of LRRC23. A mutant mouse model mimicking this variant produces a truncated LRRC23 at the C-terminus that fails to localize to the sperm tail, causing male infertility due to defective sperm motility. LRRC23 was previously proposed to be an ortholog of the RS stalk protein RSP15. However, we found that purified recombinant LRRC23 interacts with an RS head protein RSPH9, which is abolished by the C-terminal truncation. Evolutionary and structural comparison also shows that LRRC34, not LRRC23, is the RSP15 ortholog. Cryo-electron tomography clearly revealed that the absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Our study provides new insights into the structure and function of RS3 in mammalian spermatozoa and the molecular pathogenicity of LRRC23 underlying reduced sperm motility in infertile human males.
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spelling pubmed-99801782023-03-03 LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility Hwang, Jae Yeon Chai, Pengxin Nawaz, Shoaib Choi, Jungmin Lopez-Giraldez, Francesc Hussain, Shabir Bilguvar, Kaya Mane, Shrikant Lifton, Richard P. Ahmad, Wasim Zhang, Kai Chung, Jean-Ju bioRxiv Article Radial spokes (RS) are T-shaped multiprotein complexes on the axonemal microtubules. Repeated RS1, RS2, and RS3 couple the central pair to modulate ciliary and flagellar motility. Despite the cell type specificity of RS3 substructures, their molecular components remain largely unknown. Here, we report that a leucine-rich repeat-containing protein, LRRC23, is an RS3 head component essential for its head assembly and flagellar motility in mammalian spermatozoa. From infertile male patients with defective sperm motility, we identified a splice site variant of LRRC23. A mutant mouse model mimicking this variant produces a truncated LRRC23 at the C-terminus that fails to localize to the sperm tail, causing male infertility due to defective sperm motility. LRRC23 was previously proposed to be an ortholog of the RS stalk protein RSP15. However, we found that purified recombinant LRRC23 interacts with an RS head protein RSPH9, which is abolished by the C-terminal truncation. Evolutionary and structural comparison also shows that LRRC34, not LRRC23, is the RSP15 ortholog. Cryo-electron tomography clearly revealed that the absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Our study provides new insights into the structure and function of RS3 in mammalian spermatozoa and the molecular pathogenicity of LRRC23 underlying reduced sperm motility in infertile human males. Cold Spring Harbor Laboratory 2023-09-01 /pmc/articles/PMC9980178/ /pubmed/36865175 http://dx.doi.org/10.1101/2023.02.25.530050 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Hwang, Jae Yeon
Chai, Pengxin
Nawaz, Shoaib
Choi, Jungmin
Lopez-Giraldez, Francesc
Hussain, Shabir
Bilguvar, Kaya
Mane, Shrikant
Lifton, Richard P.
Ahmad, Wasim
Zhang, Kai
Chung, Jean-Ju
LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title_full LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title_fullStr LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title_full_unstemmed LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title_short LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
title_sort lrrc23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980178/
https://www.ncbi.nlm.nih.gov/pubmed/36865175
http://dx.doi.org/10.1101/2023.02.25.530050
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