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<p>Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) is a critical cytosolic DNA sensor, whose activity can be regulated by acetylation. Here, we show that nicotinamide adenine dinucleotide (NAD<sup>+</sup>)-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune responses triggered by DNA viruses or cytoplasmic DNA. Overexpression of SIRT4 inhibits HSV-1 infection, whereas knockdown of <i>SIRT4</i> has the opposite effect. Deficiency of <i>SIRT4</i>, or treatment with a SIRT4 inhibitor, impairs antiviral innate immune signaling in response to DNA viruses or cytoplasmic DNA, both in vitro and in vivo. Moreover, SIRT4 inhibitor treatment attenuates type I interferon signaling in <i>Trex1</i>-deficient cells and in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). Mechanistically, SIRT4 deacetylates cGAS and enhances its association with double‑stranded DNA. Collectively, our study identifies SIRT4 as a positive regulator of cGAS-mediated innate immune signaling pathways, which advances the understanding of the regulation of cGAS activity.</p>

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SIRT4 regulates antiviral and autoimmune responses by promoting cGAS-mediated signaling pathways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Bo Yang,
  • Yanjie Zhang,
  • Saiyu Wang,
  • Yufei Wu,
  • Zilu Diao,
  • Qunmei Zhang,
  • Chen Lu,
  • Mengyang Shen,
  • Xuewei Zhang,
  • Shujun Ma,
  • Chunsheng Yang,
  • Jinyong Pei,
  • Hongxia Xing,
  • Yinming Liang,
  • Jie Wang

摘要

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) is a critical cytosolic DNA sensor, whose activity can be regulated by acetylation. Here, we show that nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune responses triggered by DNA viruses or cytoplasmic DNA. Overexpression of SIRT4 inhibits HSV-1 infection, whereas knockdown of SIRT4 has the opposite effect. Deficiency of SIRT4, or treatment with a SIRT4 inhibitor, impairs antiviral innate immune signaling in response to DNA viruses or cytoplasmic DNA, both in vitro and in vivo. Moreover, SIRT4 inhibitor treatment attenuates type I interferon signaling in Trex1-deficient cells and in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). Mechanistically, SIRT4 deacetylates cGAS and enhances its association with double‑stranded DNA. Collectively, our study identifies SIRT4 as a positive regulator of cGAS-mediated innate immune signaling pathways, which advances the understanding of the regulation of cGAS activity.