TY  - JOUR
AU  - Acharya, Dhiraj
AU  - Sayyad, Zuberwasim
AU  - Hoenigsperger, Helene
AU  - Hirschenberger, Maximilian
AU  - Zurenski, Matthew
AU  - Balakrishnan, Kannan
AU  - Zhu, Junji
AU  - Gableske, Sebastian
AU  - Kato, Jiro
AU  - Zhang, Shen-Ying
AU  - Casanova, Jean-Laurent
AU  - Moss, Joel
AU  - Sparrer, Konstantin M J
AU  - Gack, Michaela U
TI  - TRIM23 mediates cGAS-induced autophagy in anti-HSV defense.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00610
SP  - 4418
PY  - 2025
AB  - 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.
KW  - Autophagy: immunology
KW  - Humans
KW  - Nucleotidyltransferases: metabolism
KW  - Nucleotidyltransferases: genetics
KW  - Nucleotidyltransferases: immunology
KW  - Herpesvirus 1, Human: immunology
KW  - Herpesvirus 1, Human: physiology
KW  - Protein Serine-Threonine Kinases: metabolism
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Animals
KW  - Phosphorylation
KW  - Fibroblasts: metabolism
KW  - Fibroblasts: virology
KW  - Mice
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Herpes Simplex: immunology
KW  - Herpes Simplex: virology
KW  - HEK293 Cells
KW  - Signal Transduction
KW  - Ubiquitination
KW  - Nucleotidyltransferases (NLM Chemicals)
KW  - Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - cGAS protein, human (NLM Chemicals)
KW  - TBK1 protein, human (NLM Chemicals)
KW  - STING1 protein, human (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - cGAS protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40360474
C2  - pmc:PMC12075517
DO  - DOI:10.1038/s41467-025-59338-5
UR  - https://pub.dzne.de/record/278654
ER  -