RNF220 safeguards meiotic synapsis and male fertility by antagonizing SYCE1 ubiquitination

A homozygous mutation in RNF220, encoding a RING-type E3 ubiquitin ligase, is associated with male infertility featuring small-headed sperm, but the precise roles and mechanisms of RNF220 in spermatogenesis remain elusive. Here, we explored the function of RNF220 in spermatogenesis using a Stra8-Cre-mediated germ cell-specific conditional knockout mouse model. RNF220 was highly expressed in mouse spermatocytes, and its germ cell-specific deletion caused male subfertility, accompanied by testicular atrophy, oligozoospermia, and abnormal sperm morphology. Spermatocyte nuclear spreading assay revealed severe defects in homologous chromosome synapsis and DNA damage repair, as well as elevated apoptosis in pachytene spermatocytes. Mechanistically, SYCE1, a core component of the synaptonemal complex central element essential for synapsis, was identified as a testicular target of RNF220. Notably, RNF220 stabilized SYCE1 by antagonizing its ubiquitination mediated by other ubiquitin ligases. RNF220 deficiency led to reduced SYCE1 protein level and marked increase in its K48-linked polyubiquitination. Furthermore, RNF220-mediated SYCE1 stabilization was independent of its intrinsic ubiquitin ligase activity. Our findings define the essential role of RNF220 in spermatogenesis and provide novel molecular insights into the pathogenesis of male infertility.