Alternative cGAS signaling promotes herpes simplex encephalitis

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson's disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-27
DOI
https://doi.org/10.1073/pnas.2423873122
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Alternative cGAS signaling promotes herpes simplex encephalitis

John Bertin, Zhaozhao Jiang, Viera Kasparcova, Evelyn A. Kurt‐Jones et al.
Proceedings of the National Academy of Sciences
interferon and immune responses
article

Alternative cGAS signaling promotes herpes simplex encephalitis

John Bertin, Zhaozhao Jiang, Viera Kasparcova, Evelyn A. Kurt‐Jones, Joshi M. Ramanjulu, Sara Cahill, Katherine A. Fitzgerald, Sze‐Ling Ng, Ruth Wilson, Fiachra Humphries, Richard K. Kandasamy, G. Scott Pesiridis, Laurel Stine, Liraz Shmuel-Galia
article en

Abstract

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson's disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.

Proceedings of the National Academy of SciencesVol. 122(22)
University of Massachusetts Chan Medical School (US), Norwegian University of Science and Technology (NO), GlaxoSmithKline (India) (IN), GlaxoSmithKline (United States) (US), Inflammation Research Foundation (US), Sanofi (Mexico) (MX)
Charles H. Hood Foundation, Crohn's and Colitis Foundation, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 87%
interferon and immune responses
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.