G3BP1 Inhibition Alleviates Intracellular Nucleic Acid–Induced Autoimmune Responses

Abstract

The detection of intracellular nucleic acids is a fundamental mechanism of host defense against infections. The dysregulated nucleic acid sensing, however, is a major cause for a number of autoimmune diseases. In this study, we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for both intracellular DNA- and RNA-induced immune responses. We found that in both human and mouse cells, the deletion of G3BP1 led to the dampened cGAS activation by DNA and the insufficient binding of RNA by RIG-I. We further found that resveratrol (RSVL), a natural compound found in grape skin, suppressed both intracellular DNA- and RNA-induced type I IFN production through inhibiting G3BP1. Importantly, using experimental mouse models for Aicardi–Goutières syndrome, an autoimmune disorder found in humans, we demonstrated that RSVL effectively alleviated intracellular nucleic acid–stimulated autoimmune responses. Thus, our study demonstrated a broader role of G3BP1 in sensing different kinds of intracellular nucleic acids and presented RSVL as a potential treatment for autoimmune conditions caused by dysregulated nucleic acid sensing.

Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner

“…Our group and others have recently shown that G3BP1 is sequestered within replication complexes in infected cells [34,66,67]. Since it was also recently shown to contribute to DNA sensing by cGAS [68][69][70], it is entirely possible that its sequestration in replication complexes also dampens its contribution to cGAS activation. Further work is however required to determine if this is the case.…”

cGAS inhibition alleviates Alu RNA-induced immune responses and cytotoxicity in retinal pigmented epithelium

“…EGCG and RSVL were respectively showed to inhibit the activation of cGAS [ 16 , 21 ]. We therefore examined their effects in ARPE-19 cells.…”

“…It is therefore suggested that cGAS inhibition may be a potential mean to preserve RPE health and to treat GA. Several cGAS inhibitors were identified recently. For example, two natural chemicals, epigallocatechin gallate (EGCG) [ 16 ] and resveratrol (RSVL) [ 21 ], were showed to suppress cGAS activation efficiently. In the current study, we explored whether these cGAS-inhibiting reagents could be used to ameliorate the Alu RNAs-induced immune responses and cell death in RPE.…”

Pharmacological inhibition of TBK1/IKKε blunts COVID-19 immunopathology

“…Flavonoids are a highly diverse class of plant metabolites with a wide range of health benefits including widespread anti-inflammatory effects 12,13 . Recent evidence suggests that a select subset of flavonoid and related compounds (e.g., epigallocatechin gallate and resveratrol), can inhibit the cGAS-STING pathway in autoimmune diseases 14,15 . We therefore performed a selective screen on four flavonoids (using resveratrol as a positive control) to examine if other flavonoid compounds also impact STING signalling.…”

“…Tomalika R. Ullah 1,2,15 , Matt D. Johansen 3,15 , Katherine R. Balka 4 , Rebecca L. Ambrose 1,2 , Linden J. Gearing 1,2 , Daniel Wenholz 5 , Jun Zeng 6 , Stefan Miemczyk 3 , Duc H. Nguyen 3 , Nicole G. Hansbro 3 , Rajan Venkatraman 4 , Matthew L. Dennis 7,8 , Arwaf S. Alharbi 1,2 , Julia I. Ellyard 9,10 , Wilson Wong 1,2,11 , Naresh Kumar 12 , Benjamin T. Kile 4,13 , Carola G. Vinuesa 9,10,14 , Graham E. Kelly 5 , Philip M. Hansbro 3 , Olivier F. Laczka 5 , Dominic De Nardo…”