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<p>Melanoma Differentiation-Associated gene 5 (MDA5) serves as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (PAMPs), making it instrumental in antiviral defense. However, its non-canonical role in adaptive immunity, particularly in regulating B-cell immune functions,&#xa0;is poorly characterized. Here, we demonstrate that MDA5 is critical for the marginal zone (MZ) B-cell differentiation, B-cell receptor (BCR) signal transduction, and cytoskeletal dynamics. We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in <i>Mda5</i> knockout (KO) B cells can be rescued by the treatment with the dynamin1 (DNM1) activator Bis-T-23. Furthermore, MDA5 deficiency induces metabolic perturbations in B cells, characterized by a reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), excessive reactive oxygen species (ROS) accumulation, and increased mitochondrial fission. Notably, taurine levels are decreased in <i>Mda5</i> KO B cells, and in vitro taurine supplementation rescues impaired BCR signaling. Finally, MDA5-deficient mice exhibit a blunted humoral immune response. Overall, this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation, BCR signaling, and the humoral immune response.</p><p></p>

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MDA5 regulates BCR signaling and B-cell function via NF-κB-mediated DNM1

  • 期刊论文

  • 发表日期：

    2026年1月1日

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  • Li Luo,
  • Yi Wang,
  • Guofeng Fang,
  • Jiang Chang,
  • Xin Dai,
  • Heng Gu,
  • Yanmei Huang,
  • Heather Miller,
  • Yue Li,
  • Ran Chen,
  • Ju Liu,
  • Yukai Jing,
  • Panpan Jiang,
  • Lu Yang,
  • Qianglin Chen,
  • Jingzhi Yang,
  • Xi Luo,
  • Danqing Kang,
  • Qi Liu,
  • Juan Lai,
  • Pengwei Xu,
  • Huawei Mao,
  • Xiufen Hu,
  • Xingrong Du,
  • Jiahui Lei,
  • Xiuran Tang,
  • Weibing Kuang,
  • Cheng Wu,
  • Zhanguo Li,
  • Zhenli Huang,
  • Wanli Liu,
  • Chaohong Liu

摘要

Melanoma Differentiation-Associated gene 5 (MDA5) serves as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (PAMPs), making it instrumental in antiviral defense. However, its non-canonical role in adaptive immunity, particularly in regulating B-cell immune functions, is poorly characterized. Here, we demonstrate that MDA5 is critical for the marginal zone (MZ) B-cell differentiation, B-cell receptor (BCR) signal transduction, and cytoskeletal dynamics. We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout (KO) B cells can be rescued by the treatment with the dynamin1 (DNM1) activator Bis-T-23. Furthermore, MDA5 deficiency induces metabolic perturbations in B cells, characterized by a reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), excessive reactive oxygen species (ROS) accumulation, and increased mitochondrial fission. Notably, taurine levels are decreased in Mda5 KO B cells, and in vitro taurine supplementation rescues impaired BCR signaling. Finally, MDA5-deficient mice exhibit a blunted humoral immune response. Overall, this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation, BCR signaling, and the humoral immune response.