LRRC71 stabilizes SEPT4 protein to ensure sperm annulus integrity and male fertility

Jinmei Cheng; Yu Wang; Yueming Wang; Zifeng Chen; Hehe Ren; Jiahui Li; Yifan Liang; Mingzhe Yang; Yashi Fan; Ziyi Luo; Yitian Xie; Ziqian Qi; Guishuan Wang; Yinchuan Li; Fei Sun

doi:10.1016/j.jgg.2026.07.008

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LRRC71 stabilizes SEPT4 protein to ensure sperm annulus integrity and male fertility

doi: 10.1016/j.jgg.2026.07.008

a. Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China;
b. School of Basic Medical Sciences, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia 750004, China

Funds:

We are grateful to Prof. Mofang Liu and Dr. Tuo Pan (Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Shanghai, China) for providing pLV-IRES-CytoIV-EGFP and technical guidance of lentivirus injection. We thank Li Liu at Nanjing Medical University for technical assistance on ICSI.We thank Li Wang and Dandan Song in the Center of Cryo-Electron Microscopy at Zhejiang University for their technical assistance on transmission electron microscopy and scanning electron microscopy. This study was supported by the National Key Research and Development Program of China (2024YFC2706800), the National Natural Science Foundation of China (U24A20657 and 82371613), the Natural Science Foundation of Jiangsu Province (BK20251912), and the Large Instruments and Equipment Open Fund of Nantong University.

Received Date: 2026-04-30
Accepted Date: 2026-07-18
Rev Recd Date: 2026-07-14

Available Online: 2026-07-27

Abstract

Abstract

The structural integrity of the sperm flagellum is essential for male fertility, and its impairment is associated with reduced sperm motility. The sperm annulus is a septin-based fibrous ring that demarcates the midpiece and the principal piece. Notably, defects in sperm annulus formation frequently co-occur with abnormalities in flagellar structure; however, the underlying molecular mechanisms remain poorly understood. Herein, we identify an evolutionarily conserved leucine-rich repeat-containing protein, LRRC71, and show that its deficiency results in spermatozoa with a shortened mitochondrial sheath and a defective annulus, ultimately leading to male infertility. Further analysis reveals that LRRC71 deficiency leads to reduced sperm motility and decreased ATP levels following capacitation, effects that are potentially driven by a metabolic shift from oxidative phosphorylation to glycolysis. In addition, the protein levels of SEPT4, SEPT5, and SEPT7 are significantly reduced in Lrrc71-null spermatids. Mechanistically, LRRC71 directly binds SEPT4 via its N-terminal domain, thereby stabilizing the sperm annulus. Furthermore, the exogenous expression of SEPT4 rescues both motility and annulus defects in Lrrc71-null spermatozoa, confirming this functional hierarchy. Collectively, our findings demonstrate that LRRC71 serves as a central hub stabilizing sperm annulus integrity, providing insights into the pathogenic mechanisms underlying infertility associated with downregulation of LRRC71 in humans.
- LRRC71,
- SEPT4,
- Sperm annulus,
- Mitochondria,
- Male fertility

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