The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility

Xin Wang^#^{1

2}, Di-Hang Lin^#², Yue Yan^#², An-Hui Wang^#³, Jiaoyang Liao^#², Qian Meng^#⁴, Wen-Qing Yang^#⁵, Heng Zuo², Min-Min Hua^{2

6}, Fengjuan Zhang², Hongwen Zhu⁴, Hu Zhou⁴, Tian-Yu Huang², Rui He⁷, Guangyong Li⁸, Yue-Qiu Tan⁹, Hui-Juan Shi⁶, Lan-Tao Gou², Dangsheng Li², Ligang Wu², Yonggang Zheng¹⁰, Xiang-Dong Fu¹¹, Jinsong Li^{1

2

5}, Rujuan Liu¹², Guo-Hui Li¹³, Mo-Fang Liu^{14

15

16}

Affiliations

¹ 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, 310024, China.
² State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
³ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
⁴ Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁶ NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, 200032, China.
⁷ Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
⁸ Department of Urology, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, 750004, China.
⁹ Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, 410000, China.
¹⁰ Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
¹¹ Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, 310024, China.
¹² School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. liurj@shanghaitech.edu.cn.
¹³ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China. ghli@dicp.ac.cn.
¹⁴ 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, 310024, China. mfliu@sibcb.ac.cn.
¹⁵ State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China. mfliu@sibcb.ac.cn.
¹⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. mfliu@sibcb.ac.cn.

^# Contributed equally.

PMID: 37335463
DOI: 10.1007/s11427-023-2390-5

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility

Xin Wang et al. Sci China Life Sci. 2023 Jul.

. 2023 Jul;66(7):1459-1481.

doi: 10.1007/s11427-023-2390-5. Epub 2023 Jun 15.

Authors

Affiliations

¹ 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, 310024, China.
² State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
³ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
⁴ Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁶ NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, 200032, China.
⁷ Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
⁸ Department of Urology, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, 750004, China.
⁹ Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, 410000, China.
¹⁰ Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
¹¹ Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, 310024, China.
¹² School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. liurj@shanghaitech.edu.cn.
¹³ Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China. ghli@dicp.ac.cn.
¹⁴ 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, 310024, China. mfliu@sibcb.ac.cn.
¹⁵ State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China. mfliu@sibcb.ac.cn.
¹⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. mfliu@sibcb.ac.cn.

^# Contributed equally.

PMID: 37335463
DOI: 10.1007/s11427-023-2390-5

Abstract

PIWI-clade proteins harness piRNAs of 24-33 nt in length. Of great puzzles are how PIWI-clade proteins incorporate piRNAs of different sizes and whether the size matters to PIWI/piRNA function. Here we report that a PIWI-Ins module unique in PIWI-clade proteins helps define the length of piRNAs. Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter piRNAs and causes spermiogenic failure in mice, demonstrating the functional importance of this regulatory module. Mechanistically, we show that longer piRNAs provide additional complementarity to target mRNAs, thereby enhancing the assembly of the MIWI/eIF3f/HuR super-complex for translational activation. Importantly, we identify a c.1108C>T (p.R370W) mutation of HIWI (human PIWIL1) in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer piRNAs. These findings reveal a critical role of PIWI-Ins-ensured longer piRNAs in fine-tuning MIWI/piRNA targeting capacity, proven essential for spermatid development and male fertility.

Keywords: PIWI; PIWI-Ins; male fertility; piRNAs; spermatid development; translational activation.

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References

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The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility

Affiliations

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility

Authors

Affiliations

Abstract

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous