The COX2-PGE₂-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.

IF 7.7 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2026-10-27 Epub Date: 2026-10-16 DOI:10.1016/j.celrep.2026.118154

Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Juliette A Bokor, Vasiliya Kril, Cara Schiavon, Scott B Biering, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind

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引用次数: 0

Abstract

The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE₂-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE₂ acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE₂ signaling and mtDNA-dependent STING activation and identify the COX2-PGE₂-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.

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COX2-PGE2-PKA轴通过抑制mtdna依赖性STING激活来抑制抗病毒免疫。

干扰素基因刺激因子（STING）通路对于增强先天免疫至关重要，但其慢性激活可导致有害炎症。尽管已经报道了多种抑制STING信号传导的细胞自主机制，但组织微环境中的炎症介质是否调节STING激活仍然难以捉摸。利用1型单纯疱疹病毒感染作为STING激活的模型，我们发现COX2-PGE2-PKA轴在STING介导的抗病毒先天免疫中起关键负调控作用。在机制上，PGE2通过EP4-PKA级联作用，通过磷酸化STOML2的Ser29位点，诱导pten诱导的激酶1 （PINK1）介导的有丝分裂。这一途径有助于清除作为免疫刺激细胞质线粒体DNA来源的受损线粒体，从而减弱下游STING激活和I型干扰素，同时促进病毒复制。总之，这些发现确立了线粒体质量控制是PGE2信号和mtdna依赖性STING激活之间的机制联系，并确定了cox -PGE2- pka途径是增强STING介导的先天免疫的可药物治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.