Alternative cGAS signaling promotes herpes simplex encephalitis
成果类型：
Article
署名作者：
Shmuel-Galia, Liraz; Jiang, Zhaozhao; Stine, Laurel; Cahill, Sara; Ng, Sze - Ling; Wilson, Ruth; Kandasamy, Richard Kumaran; Kurt-Jones, Evelyn A.; Ramanjulu, Joshi M.; Bertin, John; Kasparcova, Viera; Pesiridis, G. Scott; Fitzgerald, Katherine A.; Humphries, Fiachra
署名单位：
University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School; GlaxoSmithKline; Glaxosmithkline USA; Norwegian University of Science & Technology (NTNU); Norwegian University of Science & Technology (NTNU); University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Sanofi-Aventis; Sanofi USA
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-10346
DOI：
10.1073/pnas.2423873122
发表日期：
2025-06-03
关键词：
cyclic gmp-amp
structural basis
sting pathway
i interferon
dna sensor
activation
2nd-messenger
dinucleotide
synthase
tlr2
摘要：
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-Gouti & egrave;res 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.