biostudies-literatureZhang ZNational Natural Science Foundation of China (National Science Foundation of China)59https://www.ebi.ac.uk/biostudies/studies/S-EPMC12913675biostudies-literatureUnknown11(1)The development and function of B lymphocytes require the precise integration of signaling, transcriptional networks, and metabolic programs. While interferon (IFN)-inducible proteins can bridge innate and adaptive immunity, their roles in B cells remain poorly defined. Here, we identified RNF213, a giant IFN-inducible RING finger E3 ligase, as a key orchestrator of B-cell biology. Mice lacking Rnf213 exhibited defective splenic B-cell development, impaired B-cell receptor (BCR) signaling, and compromised metabolic activity. Mechanistically, RNF213 targeted the transcription factor SPIB for proteasomal degradation via K11-linked ubiquitylation. In Rnf213‑deficient B cells, stabilized SPIB transcriptionally upregulated Pik3c3, thereby increasing phosphatidylinositol 3-phosphate (PI3P) production. Excess PI3P recruited PTEN to early endosomes, where PTEN hydrolyzed phosphatidylinositol-3,4,5-trisphosphate (PIP3) and attenuated AKT-mTOR signaling. Strikingly, both genetic deletion of Spib and pharmacological inhibition of PIK3C3 restored AKT-mTOR activation, metabolic fitness, and B-cell development in Rnf213-null mice. Furthermore, Rnf213 deficiency impaired both T-independent and T-dependent antibody responses, highlighting its critical role in humoral immunity. Overall, our work reveals a novel ubiquitin-dependent circuit that links interferon signaling to the transcriptional and metabolic control of B-cell homeostasis. This study also establishes RNF213 as a crucial bridge between innate immune sensing and the dynamic regulation of lymphocyte development.Signal transduction and targeted therapyRing finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes.PMC1291367532311530061Liu JYang LLiang YLiu QZhang LXiang NWang LYang XLu LLi YZhang ZQi XLiu CfalseRing finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes.The development and function of B lymphocytes require the precise integration of signaling, transcriptional networks, and metabolic programs. While interferon (IFN)-inducible proteins can bridge innate and adaptive immunity, their roles in B cells remain poorly defined. Here, we identified RNF213, a giant IFN-inducible RING finger E3 ligase, as a key orchestrator of B-cell biology. Mice lacking Rnf213 exhibited defective splenic B-cell development, impaired B-cell receptor (BCR) signaling, and compromised metabolic activity. Mechanistically, RNF213 targeted the transcription factor SPIB for proteasomal degradation via K11-linked ubiquitylation. In Rnf213‑deficient B cells, stabilized SPIB transcriptionally upregulated Pik3c3, thereby increasing phosphatidylinositol 3-phosphate (PI3P) production. Excess PI3P recruited PTEN to early endosomes, where PTEN hydrolyzed phosphatidylinositol-3,4,5-trisphosphate (PIP3) and attenuated AKT-mTOR signaling. Strikingly, both genetic deletion of Spib and pharmacological inhibition of PIK3C3 restored AKT-mTOR activation, metabolic fitness, and B-cell development in Rnf213-null mice. Furthermore, Rnf213 deficiency impaired both T-independent and T-dependent antibody responses, highlighting its critical role in humoral immunity. Overall, our work reveals a novel ubiquitin-dependent circuit that links interferon signaling to the transcriptional and metabolic control of B-cell homeostasis. This study also establishes RNF213 as a crucial bridge between innate immune sensing and the dynamic regulation of lymphocyte development.2026-01-01T00:00:00Z2026 Feb2026-07-09T11:10:36.436Z2026-07-09T10:42:33.717ZS-EPMC129136754170288410.1038/s41392-026-02575-x