Abstract
Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1-cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA-induced autoinflammatory responses in an Aicardi-Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantigens / immunology
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Autoantigens / metabolism
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Autoimmune Diseases of the Nervous System / drug therapy
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Autoimmune Diseases of the Nervous System / genetics
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Autoimmune Diseases of the Nervous System / metabolism*
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Catechin / analogs & derivatives
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Catechin / therapeutic use
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Clustered Regularly Interspaced Short Palindromic Repeats
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Cytosol / immunology
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Cytosol / metabolism
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DNA / immunology
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DNA / metabolism
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DNA Helicases / antagonists & inhibitors
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Disease Models, Animal
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Exodeoxyribonucleases / genetics
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HEK293 Cells
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HeLa Cells
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Humans
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Interferons / metabolism
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Mice
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Mice, Knockout
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Multiprotein Complexes / metabolism*
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Nervous System Malformations / drug therapy
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism*
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Neuroprotective Agents / therapeutic use
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Nucleotidyltransferases / metabolism*
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Phosphoproteins / genetics
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Poly-ADP-Ribose Binding Proteins / antagonists & inhibitors
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Poly-ADP-Ribose Binding Proteins / genetics
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Poly-ADP-Ribose Binding Proteins / metabolism*
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Protein Binding
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RNA Helicases / antagonists & inhibitors
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RNA Helicases / genetics
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RNA Helicases / metabolism*
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RNA Recognition Motif Proteins / antagonists & inhibitors
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RNA Recognition Motif Proteins / genetics
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RNA Recognition Motif Proteins / metabolism*
Substances
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Autoantigens
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Multiprotein Complexes
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Neuroprotective Agents
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Phosphoproteins
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Poly-ADP-Ribose Binding Proteins
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RNA Recognition Motif Proteins
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Catechin
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DNA
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Interferons
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epigallocatechin gallate
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Nucleotidyltransferases
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cGAS protein, mouse
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Exodeoxyribonucleases
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three prime repair exonuclease 1
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DNA Helicases
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G3bp1 protein, mouse
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RNA Helicases
Supplementary concepts
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Aicardi-Goutieres syndrome