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TRIM23 mediates cGAS-induced autophagy in anti-HSV defense

Author

Listed:
  • Dhiraj Acharya

    (Cleveland Clinic
    The University of Chicago)

  • 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
    Eisai GmbH)

  • Jiro Kato

    (National Institutes of Health)

  • Shen-Ying Zhang

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute)

  • Jean-Laurent Casanova

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute
    Howard Hughes Medical Institute)

  • Joel Moss

    (National Institutes of Health)

  • Konstantin M. J. Sparrer

    (Ulm University Medical Center
    German Center for Neurodegenerative Diseases (DZNE))

  • Michaela U. Gack

    (Cleveland Clinic
    The University of Chicago)

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.

Suggested Citation

  • Dhiraj Acharya & Zuberwasim Sayyad & Helene Hoenigsperger & Maximilian Hirschenberger & Matthew Zurenski & Kannan Balakrishnan & Junji Zhu & Sebastian Gableske & Jiro Kato & Shen-Ying Zhang & Jean-Lau, 2025. "TRIM23 mediates cGAS-induced autophagy in anti-HSV defense," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59338-5
    DOI: 10.1038/s41467-025-59338-5
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