TRIM23 mediates cGAS-induced autophagy in anti-HSV defense

作者：Dhiraj Acharya, Zuberwasim Sayyad, Helene Hoenigsperger, Maximilian Hirschenberger, Matthew A. Zurenski, Kannan Balakrishnan, Junji Zhu, Sebastian Gableske, Jiro Kato, Shen‐Ying Zhang, Jean‐Laurent Casanova, Joel Moss, Konstantin M. J. Sparrer, Michaela U. Gack · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59338-5 · 被引用次数：12 · 研究领域：interferon and immune responses、Toxoplasma gondii Research Studies、Cytomegalovirus and herpesvirus research

The cGAS-STING pathway, well-known to elicit interferon (IFN) responses, is also a key inducer of autophagy upon virus infection or other stimuli. Whereas the mediators for cGAS-induced IFN responses are well characterized, much less is known about how cGAS elicits autophagy. Here, we report that TRIM23, a unique TRIM protein harboring both ubiquitin E3 ligase and GTPase activity, is crucial for cGAS-STING-dependent antiviral autophagy. Genetic ablation of TRIM23 impairs autophagic control of HSV-1 infection. HSV-1 infection or cGAS-STING stimulation induces TBK1-mediated TRIM23 phosphorylation at S39, which triggers TRIM23 autoubiquitination and GTPase activity and ultimately elicits autophagy. Fibroblasts from a patient with herpes simplex encephalitis heterozygous for a dominant-negative, kinase-inactivating TBK1 mutation fail to activate autophagy by TRIM23 and cGAS-STING. Our results thus identify the cGAS-STING-TBK1-TRIM23 axis as a key autophagy defense pathway and may stimulate new therapeutic interventions for viral or inflammatory diseases. The cGAS-STING pathway senses cytosolic DNA to activate interferon responses, but has also been implicated in autophagy induction. Here the authors show that, during herpes simplex virus infection, cGAS-induced autophagy is mediated by TBK1-induced TRIM23 phosphorylation and downstream signaling events to assist in antiviral immunity.