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

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.