STING trafficking activates MAPK-CREB signaling to trigger regulatory T cell differentiation

• 成果类型: Article
• 署名作者: Lin, Wei; Szaboa, Claudia; Liu, Tao; Tao, Huangheng; Wu, Xianfang; Wu, Jianjun
• 署名单位: Cleveland Clinic Foundation; Cleveland Clinic Foundation
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11604
• DOI: 10.1073/pnas.2320709121
• 发表日期: 2024-07-16
• 关键词: cyclic gmp-amp; decamer motif; transcription; autoimmunity; promoter; adapter; kinase; loop

摘要

The Type- I interferon (IFN-I)- I) response is the major outcome of stimulator of interferon genes (STING) activation in innate cells. STING is more abundantly expressed in adaptive T cells; nevertheless, its intrinsic function in T cells remains unclear. Intriguingly, we previously demonstrated that STING activation in T cells activates widespread IFN-- independent activities, which stands in contrast to the well- known STING-- mediated IFN response. Here, we have identified that STING activation induces regulatory T cells (Tregs) differentiation independently of IRF3 and IFN. Specifically, the translocation of STING from the endoplasmic reticulum to the Golgi activates mitogen-- activated protein kinase (MAPK) activity, which subsequently triggers transcription factor cAMP response element-- binding protein (CREB) activation. The activation of the STING-MAPK-CREB signaling pathway induces the expression of many cytokine genes, including interleukin-2- 2 (IL- 2) and transforming growth factor- beta (TGF-beta 2),-beta 2), to promote the Treg differentiation. Genetic knockdown of MAPK p38 or pharmacological inhibition of MAPK p38 or CREB markedly inhibits STING-- mediated Treg differentiation. Administration of the STING agonist also promotes Treg differentiation in mice. In the Trex1-/- -/- autoimmune disease mouse model, we demonstrate that intrinsic STING activation in CD4+ T cells can drive Treg differentiation, potentially counterbalancing the autoimmunity associated with Trex1 deficiency. Thus, STING- MAPK-CREB represents an IFN-- independent signaling axis of STING that may have profound effects on T cell effector function and adaptive immunity.