Journal Article

DZNE-2025-00610

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TRIM23 mediates cGAS-induced autophagy in anti-HSV defense.

Acharya, D. ; Sayyad, Z. ; Hoenigsperger, H.Extern* ; Hirschenberger, M.Extern* ; Zurenski, M. ; Balakrishnan, K. ; Zhu, J. ; Gableske, S. ; Kato, J. ; Zhang, S.-Y. ; Casanova, J.-L. ; Moss, J. ; Sparrer, K. M. J.DZNE* ; Gack, M. U.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-59338-5

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.

Keyword(s): Autophagy: immunology (MeSH) ; Humans (MeSH) ; Nucleotidyltransferases: metabolism (MeSH) ; Nucleotidyltransferases: genetics (MeSH) ; Nucleotidyltransferases: immunology (MeSH) ; Herpesvirus 1, Human: immunology (MeSH) ; Herpesvirus 1, Human: physiology (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; Protein Serine-Threonine Kinases: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Animals (MeSH) ; Phosphorylation (MeSH) ; Fibroblasts: metabolism (MeSH) ; Fibroblasts: virology (MeSH) ; Mice (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Herpes Simplex: immunology (MeSH) ; Herpes Simplex: virology (MeSH) ; HEK293 Cells (MeSH) ; Signal Transduction (MeSH) ; Ubiquitination (MeSH) ; Nucleotidyltransferases ; Protein Serine-Threonine Kinases ; Membrane Proteins ; cGAS protein, human ; TBK1 protein, human ; STING1 protein, human ; Ubiquitin-Protein Ligases ; cGAS protein, mouse

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Acharya, D. ; Sayyad, Z. ; Hoenigsperger, H.Extern* ; Hirschenberger, M.Extern* ; Zurenski, M. ; Balakrishnan, K. ; Zhu, J. ; Gableske, S. ; Kato, J. ; Zhang, S.-Y. ; Casanova, J.-L. ; Moss, J. ; Sparrer, K. M. J.DZNE* ; Gack, M. U.
Publisher Correction: TRIM23 mediates cGAS-induced autophagy in anti-HSV defense.
Nature Communications 16(1), 6114 (2025) [10.1038/s41467-025-61557-9]2025   Files BibTeX | EndNote: XML, Text | RIS

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