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.
Jing-Mei Cha, Huijuan Lin, Yingqian Xia et al.· Cell Death & Disease· 0 citations
ABSTRACT In the central nervous system, oligodendrocytes (OLs) generate myelin sheaths to support rapid nerve impulse conduction. OL lineage cells, especially oligodendrocyte precursor cells (OPCs), feature high metabolic activity and are exposed to severe oxidative stress, but the protective mechanisms remain poorly understood. Here we show that RLIM, an E3 ubiquitin ligase linked to X‐linked neurodevelopmental disorders, safeguards OL development via ferroptosis resistance. RLIM directly polyubiquitinates SLC7A11, a key cystine/glutamate antiporter for glutathione (GSH) synthesis, thereby sustaining SLC7A11 membrane localization. OL lineage‐specific ablation of RLIM in mice reduces membrane SLC7A11, impairs OPC proliferation, and triggers ferroptosis and thus myelination defects, leading to motor, social, and cognitive deficits that mimic patient phenotypes. Most pathological RLIM missense variants disrupt SLC7A11 binding and/or polyubiquitination. Importantly, GSH supplementation rescues myelination defects and behavioral abnormalities in RLIM‐deficient mice. These findings reveal that the RLIM–SLC7A11‐GSH signaling axis governs ferroptosis resistance in OL lineage cells, implicates this pathway in RLIM‐related neurodevelopmental disorders, and suggests GSH as a potential therapeutic strategy.
Yuwei Li, Haijun Zhang, Jieya Zhou et al.· Advancement of science· 0 citations
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