The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

• Published in: The FASEB journal Vol. 34; no. 10; pp. 13156 - 13170
• Main Authors: Ma, Ruihua, Ortiz Serrano, Tatiana P., Davis, Jennifer, Prigge, Andrew D., Ridge, Karen M.
• Format: Journal Article
• Language: English
• Published: United States 01-10-2020
• Subjects: AIM2; Animals; autoimmune disease; cGAMP; DAMP; DNA - metabolism; Humans; Lung Diseases - genetics; Lung Diseases - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; pulmonary disease; Signal Transduction; AIM2; cGAMP; pulmonary disease; autoimmune disease; DAMP
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202001607R

The presence of DNA in the cytosol is usually a sign of microbial infections, which alerts the host innate immune system to mount a defense response. Cyclic GMP‐AMP synthase (cGAS) is a critical cytosolic DNA sensor that elicits robust innate immune responses through the production of the second messenger, cyclic GMP‐AMP (cGAMP), which binds and activates stimulator of interferon genes (STING). However, cGAS binds to DNA irrespective of DNA sequence, therefore, self‐DNA leaked from the nucleus or mitochondria can also serve as a cGAS ligand to activate this pathway and trigger extensive inflammatory responses. Dysregulation of the cGAS‐STING pathway is responsible for a broad array of inflammatory and autoimmune diseases. Recently, evidence has shown that self‐DNA release and cGAS‐STING pathway over‐activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Here, we review recent advances on the cGAS‐STING pathway governing self‐DNA sensing, highlighting its role in pulmonary disease.