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<p>Type I immunity, mediated by IFN-γ, is essential for combating intracellular pathogens but also drives inflammatory diseases. How the immune system balances protective type I responses with pathological inflammation is elusive. While the IL-12-STAT4 pathway that promotes IFN-γ production is well-established, the intrinsic negative regulators remain unclear. We establish that RASA3 serves as a permissive checkpoint for type I immune responses. T cell-specific ablation of RASA3 amplified Th1/Tc1 immunity and IFN-γ expression, enhancing the clearance of <i>Listeria monocytogenes</i> but exacerbating allergic contact dermatitis. We further identify the hematopoietic cell kinase (HCK) as a direct kinase for STAT4, which binds to and phosphorylates it at the Tyr693 residue to elicit IFN-γ production. Mechanistically, RASA3 represses the translation of HCK via constraining ribosomal protein RPL36A expression. Additionally, the RASA3-HCK axis is conserved in human Th1 cells. Thus, we define a critical role of the RASA3-HCK-STAT4 axis in fine-tuning type I immunity and offer promising targets for intervening in Th1/Tc1-driven pathologies.</p>

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RAS P21 Protein Activator 3 finetunes Type I immunity by limiting HCK-mediated STAT4 phosphorylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Jiayu Song,
  • Xiaoyu Liu,
  • Jie Sun,
  • Xi Cheng,
  • Chuan He,
  • Yunhong Zhong,
  • Jinfang Zhang,
  • Junjie Zhang,
  • Hui Xiong,
  • Bing Wu

摘要

Type I immunity, mediated by IFN-γ, is essential for combating intracellular pathogens but also drives inflammatory diseases. How the immune system balances protective type I responses with pathological inflammation is elusive. While the IL-12-STAT4 pathway that promotes IFN-γ production is well-established, the intrinsic negative regulators remain unclear. We establish that RASA3 serves as a permissive checkpoint for type I immune responses. T cell-specific ablation of RASA3 amplified Th1/Tc1 immunity and IFN-γ expression, enhancing the clearance of Listeria monocytogenes but exacerbating allergic contact dermatitis. We further identify the hematopoietic cell kinase (HCK) as a direct kinase for STAT4, which binds to and phosphorylates it at the Tyr693 residue to elicit IFN-γ production. Mechanistically, RASA3 represses the translation of HCK via constraining ribosomal protein RPL36A expression. Additionally, the RASA3-HCK axis is conserved in human Th1 cells. Thus, we define a critical role of the RASA3-HCK-STAT4 axis in fine-tuning type I immunity and offer promising targets for intervening in Th1/Tc1-driven pathologies.