2. Academic Validation
  3. PPP6R3-mediated dephosphorylation regulates mRNA translation during spermatogonial differentiation

PPP6R3-mediated dephosphorylation regulates mRNA translation during spermatogonial differentiation

  • Commun Biol. 2025 Jul 28;8(1):1114. doi: 10.1038/s42003-025-08539-1.
Qian Fang # 1 2 3 4 5 6 7 8 9,  Biyun Liu # 1 2 3 4 5 6 7 8,  Jie Cen 1 2 3 4 5 6 7 8,  Tongtong Li 1 2 3 4 5 6 7 8,  Shuhui Ji 10,  Wenqing Li 11,  Gang Lu 12,  Zi-Jiang Chen 13 14 15 16 17 18 19 20 21 22 23,  Xin Wang 24,  Jianqiang Bao 25,  Hongbin Liu 26 27 28 29 30 31 32 33 34
Affiliations

Affiliations

  • 1 Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, China.
  • 2 State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China.
  • 3 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.
  • 4 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China.
  • 5 Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China.
  • 6 Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China.
  • 7 Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China.
  • 8 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China.
  • 9 Suzhou Research Institute, Shandong University, Suzhou, Jiangsu, 215123, China.
  • 10 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 11 Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 12 CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, the Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 13 Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, China. chenzijiang@hotmail.com.
  • 14 State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 15 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 16 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 17 Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 18 Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 19 Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 20 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. chenzijiang@hotmail.com.
  • 21 Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China. chenzijiang@hotmail.com.
  • 22 Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China. chenzijiang@hotmail.com.
  • 23 Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. chenzijiang@hotmail.com.
  • 24 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. wx@ucas.ac.cn.
  • 25 Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China. jqbao@ustc.edu.cn.
  • 26 Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, China. hongbin_sduivf@aliyun.com.
  • 27 State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 28 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 29 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 30 Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 31 Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 32 Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 33 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. hongbin_sduivf@aliyun.com.
  • 34 Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China. hongbin_sduivf@aliyun.com.
  • # Contributed equally.
PMID: 40721635 DOI: 10.1038/s42003-025-08539-1
Abstract

Protein dephosphorylation mediated by phosphatases regulates spermatogenesis. However, which proteins are dephosphorylated and how they regulate spermatogenesis are largely unknown. Here, we show that germline-specific deletion of protein Phosphatase 6 regulatory subunit 3 (PPP6R3), which determines substrate specificity of protein Phosphatase 6 (PP6), causes abnormal spermatogonial differentiation and male infertility, accompanied by translation inhibition. PPP6R3 directly interacts with EIF3C and EIF4G1 in KIT+ spermatogonia. Decreased levels of non-phosphorylated EIF3C and EIF4G1 after PPP6R3 deletion attenuate their enrichment for mRNAs associated with spermatogonial differentiation, and increased phosphorylation levels promote their degradation. Specifically, the phosphorylation status both of EIF3CS39 and EIF4G1S1217 are significantly up-regulated in mutant mice. Overexpression of EIF3CS39A and EIF4G1S1217A mutants in Ppp6r3-cKO spermatogonial progenitor cells compensates for the deficiency of differentiation potential by upregulating translation rates of differentiation-associated mRNAs. Our findings demonstrate EIF3C and EIF4G1, as specific substrates of PPP6R3/PP6 holoenzyme, are required for translation activation during spermatogonial differentiation.

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