STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease.
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Jan
J
Petrasek
Arvin
A
Iracheta-Vellve
Timea
T
Csak
Abhishek
A
Satishchandran
Karen
K
Kodys
Evelyn A
EA
Kurt-Jones
Katherine A
KA
Fitzgerald
Gyongyi
G
Szabo
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000276:immunology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D012044:Regression Analysis; D015398:Signal Transduction / Q000276:immunology*; D014280:Triglycerides / Q000378:metabolism; D000099197:STING Protein
D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D014280:Triglycerides; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein
Kupffer cells; interferon regulatory factor 3; steatohepatitis; stimulator of interferon genes