• PMID: 28552346
• Gene Name: PIWIL1
• Condition: Spermiogenesis
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male infertility

Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis

Gou LT, Kang JY, Dai P, Wang X, Li F, Zhao S, Zhang M, Hua MM, Lu Y, Zhu Y, Li Z, Chen H, Wu LG, Li D, Fu XD, Li J, Shi HJ, Liu MF.

Genetic studies have elucidated critical roles of Piwi proteins in germline development in animals, but whether Piwi is an actual disease gene in human infertility remains unknown. We report germline mutations in human Piwi (Hiwi) in patients with azoospermia that prevent its ubiquitination and degradation. By modeling such mutations in Piwi (Miwi) knockin mice, we demonstrate that the genetic defects are directly responsible for male infertility. Mechanistically, we show that MIWI binds the histone ubiquitin ligase RNF8 in a Piwi-interacting RNA (piRNA)-independent manner, and MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology, and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatids with an RNF8-N peptide. Collectively, our findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis. CI - Copyright © 2017 Elsevier Inc. All rights reserved. FAU - Gou, Lan-Tao AU - Gou LT AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA. FAU - Kang, Jun-Yan AU - Kang JY AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Dai, Peng AU - Dai P AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Wang, Xin AU - Wang X AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Li, Feng AU - Li F AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Zhao, Shuang AU - Zhao S AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Zhang, Man AU - Zhang M AD - State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Hua, Min-Min AU - Hua MM AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Lab of Reproduction Regulation of NPFPC-Shanghai Institute of Planned Parenthood Research, Fudan University Reproduction and Development Institution, Shanghai 200032, China. FAU - Lu, Yi AU - Lu Y AD - Key Lab of Reproduction Regulation of NPFPC-Shanghai Institute of Planned Parenthood Research, Fudan University Reproduction and Development Institution, Shanghai 200032, China. FAU - Zhu, Yong AU - Zhu Y AD - Department of Andrology and PFD, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center Shanghai General Hospital, Shanghai Key Lab of Reproductive Medicine Shanghai Jiao Tong University, Shanghai, 200080, China. FAU - Li, Zheng AU - Li Z AD - Department of Andrology and PFD, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center Shanghai General Hospital, Shanghai Key Lab of Reproductive Medicine Shanghai Jiao Tong University, Shanghai, 200080, China. FAU - Chen, Hong AU - Chen H AD - Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. FAU - Wu, Li-Gang AU - Wu LG AD - State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. FAU - Li, Dangsheng AU - Li D AD - Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. FAU - Fu, Xiang-Dong AU - Fu XD AD - Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA. FAU - Li, Jinsong AU - Li J AD - State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China. FAU - Shi, Hui-Juan AU - Shi HJ AD - Key Lab of Reproduction Regulation of NPFPC-Shanghai Institute of Planned Parenthood Research, Fudan University Reproduction and Development Institution, Shanghai 200032, China. Electronic address: shihuijuan@sippr.org.cn.