TRIM23 mediates cGAS-induced autophagy in anti-HSV defense

Dhiraj Acharya, Zuberwasim Sayyad, Helene Hoenigsperger, Maximilian Hirschenberger, Matthew Zurenski, Kannan Balakrishnan, Junji Zhu, Sebastian Gableske, Jiro Kato, Shen-Ying Zhang, Jean-Laurent Casanova, Joel Moss, Konstantin M. J. Sparrer and Michaela U. Gack ()
Additional contact information
Dhiraj Acharya: Cleveland Clinic
Zuberwasim Sayyad: Cleveland Clinic
Helene Hoenigsperger: Ulm University Medical Center
Maximilian Hirschenberger: Ulm University Medical Center
Matthew Zurenski: The University of Chicago
Kannan Balakrishnan: Cleveland Clinic
Junji Zhu: Cleveland Clinic
Sebastian Gableske: The University of Chicago
Jiro Kato: National Institutes of Health
Shen-Ying Zhang: The Rockefeller University
Jean-Laurent Casanova: The Rockefeller University
Joel Moss: National Institutes of Health
Konstantin M. J. Sparrer: Ulm University Medical Center
Michaela U. Gack: Cleveland Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59338-5

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