{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang Z"],"funding":["National Natural Science Foundation of China (National Science Foundation of China)"],"pagination":["59"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12913675"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11(1)"],"pubmed_abstract":["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."],"journal":["Signal transduction and targeted therapy"],"pubmed_title":["Ring finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes."],"pmcid":["PMC12913675"],"funding_grant_id":["32311530061"],"pubmed_authors":["Liu J","Yang L","Liang Y","Liu Q","Zhang L","Xiang N","Wang L","Yang X","Lu L","Li Y","Zhang Z","Qi X","Liu C"],"additional_accession":[]},"is_claimable":false,"name":"Ring finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes.","description":"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.","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-07-09T11:10:36.436Z","creation":"2026-07-09T10:42:33.717Z"},"accession":"S-EPMC12913675","cross_references":{"pubmed":["41702884"],"doi":["10.1038/s41392-026-02575-x"]}}