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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Alternative cGAS signaling promotes herpes simplex encephalitis.

Liraz Shmuel-Galia1, Zhaozhao Jiang1, Laurel Stine1

  • 1Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605.

Proceedings of the National Academy of Sciences of the United States of America
|May 27, 2025
PubMed
Summary
This summary is machine-generated.

Cyclic GMP-AMP synthase (cGAS) has a newly discovered signaling pathway independent of cGAMP. This alternative pathway enhances CXCL1 expression and neutrophil recruitment, impacting viral infections.

Keywords:
HSVcGASinfectionmouse modeltype I IFN

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Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Foreign DNA detection by cyclic GMP-AMP synthase (cGAS) triggers immune responses.
  • Dysregulated cGAS activity is linked to autoimmune and neurodegenerative diseases.
  • The role of cGAS independent of cGAMP signaling was previously undefined.

Purpose of the Study:

  • To investigate if cGAS can signal independently of its known product, cGAMP.
  • To characterize the functional consequences of this alternative cGAS signaling pathway.

Main Methods:

  • Investigated cGAS signaling pathways.
  • Analyzed CXCL1 expression and neutrophil recruitment in response to cGAS activation.
  • Utilized a herpes simplex encephalitis model.

Main Results:

  • Identified an alternative signaling pathway utilized by cGAS, independent of cGAMP synthesis.
  • Demonstrated that this alternative pathway promotes CXCL1 hyperexpression.
  • Showed enhanced neutrophil recruitment facilitating viral dissemination in herpes simplex encephalitis.

Conclusions:

  • cGAS possesses a scaffold function, mediating signaling independently of cGAMP.
  • This alternative cGAS pathway plays a role in antiviral responses and disease pathogenesis.
  • Highlights a novel therapeutic target beyond cGAMP for cGAS-related diseases.