Absence of Rnf126 causes male infertility with multiple morphological abnormalities of the sperm flagella

作者：Shengnan Wang, Zihan Qin, Juan Liu, Jie Liu, Qiaohua Xiong, Zexiao Wei, Wang Li, Yuming Cao · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02432-w · 被引用次数：5 · 研究领域：Sperm and Testicular Function、Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities、Ubiquitin and proteasome pathways

Male infertility is primarily caused by impaired flagella development, reduced sperm count, and decreased motility. Despite the involvement of many genes in spermatogenesis, the precise processes remain unclear. The critical E3 ubiquitin ligase Rnf126 regulates essential cellular processes through ubiquitination-induced protein degradation. It plays a significant role in DNA repair, immune response, and signaling cascades, underscoring its central importance in maintaining cellular homeostasis. However, the mechanisms by which Rnf126 controls spermatogenesis are not fully understood. This research identifies Rnf126 as a crucial component in sperm flagellar biogenesis and germ cell development. Through genetic lineage tracing, we show that RNF126 is highly expressed in sperm cells and weakly expressed in Sertoli cells. The germ epithelium of RNF126 deficiencies is characterized by a loss of germ cells due to an increase in germ cell apoptosis at various stages of development, which ultimately results in vesiculation of the spermatogenic tubule. Targeting Rnf126 results in different types of germ cells reduction, infertility, and microtubule-associated motor activity failure (MMAF), characterized by spermatozoa with truncated, twisted, and malformed flagella. Detailed ultrastructural studies reveal the extent of flagellar damage in the absence of Rnf126, highlighting its critical role in maintaining flagellar stability. An important finding is the interaction between RNF126 and...