ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice
Abstract
During spermiogenesis, nuclear remodeling occurs where histones are sequentially replaced by transition proteins (TNPs) and protamines, a process essential for sperm maturation. Although the degradation of histones and TNPs is thought to be essential for sperm nuclear remodeling, the underlying mechanisms, particularly those governing TNP degradation, remain poorly understood. In this study, we investigated the role of the ankyrin repeat-containing SOCS box protein 9 (ASB9) during spermiogenesis and found that its deficiency causes TNP2 retention, leading to a failure of the histone-to-protamine transition in both humans and mice. This disruption consequently causes male infertility, characterized by sperm head malformation and impairments in fertilization and early embryonic development. Mechanistically, we found that ASB9 assembles a testis-specific Cullin-RING ligase (CRL) complex—TNP2–ASB9–ELOB/C–CUL5–RBX1—that mediates the ubiquitin-dependent degradation of TNP2 to facilitate the histone-to-protamine transition during spermiogenesis. Collectively, our study uncovers the mechanism underlying TNP2 degradation and highlights the critical role of ASB9 in male fertility through the CRL complex-mediated ubiquitination pathway, thereby expanding the fundamental understanding of nuclear remodeling during spermiogenesis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Shikun Zhao
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Gan Shen
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Tiechao Ruan
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Liangchai Zhuo
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Yan Wang
Xiang Wang
Yunchuan Tian
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Xinyao Tang
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Jun Ma
Xiaohui Jiang
Yingteng Zhang
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Chuan Jiang
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University
Anan Xie
College of Biological Sciences, University of California
Xuejun Shang
Department of Urology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
Jing Wang
Hunan Cancer Hospital Changsha China
Yihong Yang
Department of Reproduction Medical Centre, West China Second University Hospital, Sichuan University
Ying Shen
Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University