Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome
Department of Medicine, Division of Infectious Diseases and Immunology
Autophagy; Immunity, Innate; DNA, Mitochondrial; Carrier Proteins
Immunology and Infectious Disease
Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. Here we demonstrate that depletion of the autophagic proteins LC3B and beclin 1 enhanced the activation of caspase-1 and secretion of interleukin 1beta (IL-1beta) and IL-18. Depletion of autophagic proteins promoted the accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial reactive oxygen species (ROS). Cytosolic mtDNA contributed to the secretion of IL-1beta and IL-18 in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity.
DOI of Published Version
Nat Immunol. 2011 Mar;12(3):222-30. Epub 2010 Dec 12. Link to article on publisher's site
Nakahira, Kiichi; Haspel, Jeffrey Adam; Rathinam, Vijay A.K.; Lee, Seon-Jin; Dolinay, Tamas; lam, Hilaire C.; Englert, Joshua A.; Rabinovitch, Marlene; Cernadas, Manuela; Kim, Hong Pyo; Fitzgerald, Katherine A.; Ryter, Stefan W.; and Choi, Augustine M. K., "Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome" (2011). Infectious Diseases and Immunology Publications and Presentations. 106.