TRIM23 mediates cGAS-induced autophagy in anti-HSV defense
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 repor...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59338-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849334313141665792 |
|---|---|
| author | 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 Michaela U. Gack |
| author_facet | 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 Michaela U. Gack |
| author_sort | Dhiraj Acharya |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8d0f90d155524e0a9e37f5fb054a85d9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8d0f90d155524e0a9e37f5fb054a85d92025-08-20T03:45:35ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-59338-5TRIM23 mediates cGAS-induced autophagy in anti-HSV defenseDhiraj Acharya0Zuberwasim Sayyad1Helene Hoenigsperger2Maximilian Hirschenberger3Matthew Zurenski4Kannan Balakrishnan5Junji Zhu6Sebastian Gableske7Jiro Kato8Shen-Ying Zhang9Jean-Laurent Casanova10Joel Moss11Konstantin M. J. Sparrer12Michaela U. Gack13Florida Research and Innovation Center, Cleveland ClinicFlorida Research and Innovation Center, Cleveland ClinicInstitute of Molecular Virology, Ulm University Medical CenterInstitute of Molecular Virology, Ulm University Medical CenterDepartment of Microbiology, The University of ChicagoFlorida Research and Innovation Center, Cleveland ClinicFlorida Research and Innovation Center, Cleveland ClinicDepartment of Microbiology, The University of ChicagoThe Critical Care Medicine and Pulmonary Branch; National Heart, Lung, and Blood Institute, National Institutes of HealthSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityThe Critical Care Medicine and Pulmonary Branch; National Heart, Lung, and Blood Institute, National Institutes of HealthInstitute of Molecular Virology, Ulm University Medical CenterFlorida Research and Innovation Center, Cleveland ClinicAbstract 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.https://doi.org/10.1038/s41467-025-59338-5 |
| spellingShingle | 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 Michaela U. Gack TRIM23 mediates cGAS-induced autophagy in anti-HSV defense Nature Communications |
| title | TRIM23 mediates cGAS-induced autophagy in anti-HSV defense |
| title_full | TRIM23 mediates cGAS-induced autophagy in anti-HSV defense |
| title_fullStr | TRIM23 mediates cGAS-induced autophagy in anti-HSV defense |
| title_full_unstemmed | TRIM23 mediates cGAS-induced autophagy in anti-HSV defense |
| title_short | TRIM23 mediates cGAS-induced autophagy in anti-HSV defense |
| title_sort | trim23 mediates cgas induced autophagy in anti hsv defense |
| url | https://doi.org/10.1038/s41467-025-59338-5 |
| work_keys_str_mv | AT dhirajacharya trim23mediatescgasinducedautophagyinantihsvdefense AT zuberwasimsayyad trim23mediatescgasinducedautophagyinantihsvdefense AT helenehoenigsperger trim23mediatescgasinducedautophagyinantihsvdefense AT maximilianhirschenberger trim23mediatescgasinducedautophagyinantihsvdefense AT matthewzurenski trim23mediatescgasinducedautophagyinantihsvdefense AT kannanbalakrishnan trim23mediatescgasinducedautophagyinantihsvdefense AT junjizhu trim23mediatescgasinducedautophagyinantihsvdefense AT sebastiangableske trim23mediatescgasinducedautophagyinantihsvdefense AT jirokato trim23mediatescgasinducedautophagyinantihsvdefense AT shenyingzhang trim23mediatescgasinducedautophagyinantihsvdefense AT jeanlaurentcasanova trim23mediatescgasinducedautophagyinantihsvdefense AT joelmoss trim23mediatescgasinducedautophagyinantihsvdefense AT konstantinmjsparrer trim23mediatescgasinducedautophagyinantihsvdefense AT michaelaugack trim23mediatescgasinducedautophagyinantihsvdefense |