The cGAS-STING pathway as a therapeutic target in inflammatory diseases

Alexiane Decout; Jason D Katz; Shankar Venkatraman; Andrea Ablasser

doi:10.1038/s41577-021-00524-z

The cGAS-STING pathway as a therapeutic target in inflammatory diseases

Nat Rev Immunol. 2021 Sep;21(9):548-569. doi: 10.1038/s41577-021-00524-z. Epub 2021 Apr 8.

Authors

Alexiane Decout¹, Jason D Katz², Shankar Venkatraman², Andrea Ablasser³

Affiliations

¹ Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
² IFM Therapeutics, Boston, MA, USA.
³ Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. [email protected].

Abstract

The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage. Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules. Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans. Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases. Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / immunology
Animals
Autophagy
Cell Death
Cell Proliferation
DNA, Mitochondrial / genetics
DNA, Mitochondrial / metabolism
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / therapeutic use
Gain of Function Mutation
Humans
Inflammation / immunology
Inflammation / metabolism
Inflammation / therapy*
Inflammation Mediators / antagonists & inhibitors
Inflammation Mediators / immunology
Inflammation Mediators / metabolism
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / genetics
Membrane Proteins / immunology
Models, Biological
Models, Molecular
Nucleotides, Cyclic / immunology
Nucleotides, Cyclic / metabolism
Nucleotidyltransferases / antagonists & inhibitors*
Nucleotidyltransferases / genetics
Nucleotidyltransferases / immunology
Signal Transduction / drug effects
Signal Transduction / genetics
Signal Transduction / immunology

Substances

Adaptor Proteins, Signal Transducing
DNA, Mitochondrial
Enzyme Inhibitors
Inflammation Mediators
Membrane Proteins
Nucleotides, Cyclic
cyclic guanosine monophosphate-adenosine monophosphate
Nucleotidyltransferases