2. Academic Validation
  3. Ring finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes

Ring finger protein 213 regulates B-cell receptor signaling, metabolism, and development in B lymphocytes

  • Signal Transduct Target Ther. 2026 Feb 18;11(1):59. doi: 10.1038/s41392-026-02575-x.
Ziyin Zhang # 1,  Nanshu Xiang # 1,  Qian Liu 1,  Yanfeng Li 2,  Linhua Wang 3,  Xinpu Yang 3,  Ju Liu 1,  Lichen Zhang 4,  Liaoxun Lu 4,  Yinming Liang 4 5,  Lu Yang 1,  Xiaopeng Qi 6 7,  Chaohong Liu 8
Affiliations

Affiliations

  • 1 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • 2 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Clinical Molecular Immunology Center, Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China.
  • 4 School of Medical Technology, Henan Medical University, Xinxiang, Henan, China.
  • 5 Center of Disease Model and Immunology, Hunan Academy of Chinese Medicine, Changsha, China.
  • 6 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 7 State Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Changsha, China. [email protected].
  • 8 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41702884 DOI: 10.1038/s41392-026-02575-x
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.

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