CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice

Xueguang Zhang, Gelin Huang, Ting Jiang, Lanlan Meng, Tongtong Li, Guohui Zhang, Nan Wu, Xinyi Chen, Bingwang Zhao, Nana Li, Sixian Wu, Junceng Guo, Rui Zheng, Zhiliang Ji, Zhigang Xu, Zhenbo Wang, Dong Deng, Yueqiu Tan () and Wenming Xu ()
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Xueguang Zhang: Sichuan University
Gelin Huang: Sichuan University
Ting Jiang: Sichuan University
Lanlan Meng: Reproductive & Genetic Hospital of CITIC-Xiangya
Tongtong Li: Sichuan University
Guohui Zhang: Sichuan Provincial Maternity and Child Health Care Hospital
Nan Wu: Xiamen University
Xinyi Chen: Sichuan University
Bingwang Zhao: Chinese Academy of Sciences
Nana Li: Shandong University
Sixian Wu: Sichuan University
Junceng Guo: Sichuan University
Rui Zheng: Sichuan University
Zhiliang Ji: Xiamen University
Zhigang Xu: Shandong University
Zhenbo Wang: Chinese Academy of Sciences
Dong Deng: Sichuan University
Yueqiu Tan: Reproductive & Genetic Hospital of CITIC-Xiangya
Wenming Xu: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Spermiogenesis, the complex transformation of haploid spermatids into mature spermatozoa, relies on precise spatiotemporal regulation of gene expression at the post-transcriptional level. The mechanisms underlying this critical process remain incompletely understood. Here, we identify centrosomal protein 112 (CEP112) as an essential regulator of mRNA translation during this critical developmental process. Mutations in CEP112 are discovered in oligoasthenoteratospermic patients, and Cep112-deficient male mice recapitulate key phenotypes of human asthenoteratozoospermia. CEP112 localizes to the neck and atypical centrioles of mature sperm and forms RNA granules during spermiogenesis, enriching target mRNAs such as Fsip2, Cfap61, and Cfap74. Through multi-omics analyses and the TRICK reporter assay, we demonstrate that CEP112 orchestrates the translation of target mRNAs. Co-immunoprecipitation and mass spectrometry identify CEP112’s interactions with translation-related proteins, including hnRNPA2B1, EEF1A1, and EIF4A1. In vitro, CEP112 undergoes liquid-liquid phase separation, forming condensates that recruit essential proteins and mRNAs. Moreover, variants in patient-derived CEP112 disrupt phase separation and impair translation efficiency. Our results suggest that CEP112 mediates the assembly of RNA granules through liquid-liquid phase separation to control the post-transcriptional expression of fertility-related genes. This study not only clarifies CEP112’s role in spermatogenesis but also highlights the role of phase separation in translational regulation, providing insights into male infertility and suggesting potential therapeutic targets.

Date: 2024
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DOI: 10.1038/s41467-024-52705-8

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