G3BP1 Inhibition Alleviates Intracellular Nucleic Acid-Induced Autoimmune Responses

Hong Cai; Xin Liu; Feng Zhang; Qiu-Ying Han; Zhao-Shan Liu; Wen Xue; Zeng-Lin Guo; Jiang-Man Zhao; Li-Ming Sun; Na Wang; Jie Mao; Kun He; Tian Xia; Yuan Chen; Liang Chen; Ai-Ling Li; Tao Zhou; Xue-Min Zhang; Wei-Hua Li; Tao Li

doi:10.4049/jimmunol.2001111

G3BP1 Inhibition Alleviates Intracellular Nucleic Acid-Induced Autoimmune Responses

J Immunol. 2021 May 15;206(10):2453-2467. doi: 10.4049/jimmunol.2001111. Epub 2021 May 3.

Authors

Hong Cai^{1

2}, Xin Liu¹, Feng Zhang¹, Qiu-Ying Han^{1

2}, Zhao-Shan Liu¹, Wen Xue^{1

2}, Zeng-Lin Guo¹, Jiang-Man Zhao¹, Li-Ming Sun¹, Na Wang¹, Jie Mao¹, Kun He¹, Tian Xia^{1

2}, Yuan Chen¹, Liang Chen¹, Ai-Ling Li^{1

2}, Tao Zhou^{1

2}, Xue-Min Zhang^{1

2

3}, Wei-Hua Li^{4

2}, Tao Li^{4

2

3}

Affiliations

¹ State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
² Nanhu Laboratory, Jiaxing, Zhejiang Province, China.
³ School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China tli@ncba.ac.cn whli@ncba.ac.cn.

PMID: 33941659
DOI: 10.4049/jimmunol.2001111

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Autoimmunity / drug effects
Autoimmunity / genetics*
Cell Survival / drug effects
DNA Helicases / antagonists & inhibitors
DNA Helicases / deficiency*
DNA Helicases / genetics
DNA Helicases / metabolism*
Fibroblasts / metabolism
Gene Knockout Techniques
HEK293 Cells
Humans
Intracellular Space / immunology
Intracellular Space / metabolism*
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nucleic Acids / metabolism*
Poly-ADP-Ribose Binding Proteins / antagonists & inhibitors
Poly-ADP-Ribose Binding Proteins / deficiency*
Poly-ADP-Ribose Binding Proteins / genetics
Poly-ADP-Ribose Binding Proteins / metabolism*
RNA Helicases / antagonists & inhibitors
RNA Helicases / deficiency*
RNA Helicases / genetics
RNA Helicases / metabolism*
RNA Recognition Motif Proteins / antagonists & inhibitors
RNA Recognition Motif Proteins / deficiency*
RNA Recognition Motif Proteins / genetics
RNA Recognition Motif Proteins / metabolism*
Resveratrol / administration & dosage
Signal Transduction / genetics*
Signal Transduction / immunology
Transfection

Substances

Nucleic Acids
Poly-ADP-Ribose Binding Proteins
RNA Recognition Motif Proteins
DNA Helicases
G3BP1 protein, human
G3bp1 protein, mouse
RNA Helicases
Resveratrol