Regulation of dsDNA-induced innate immune responses by membrane trafficking.
Microbial nucleic acids are potent inducers of innate immune response--the first line of host defense against microbes. It is known that double-stranded (ds) DNA triggers the expression of type I interferons (IFNs) and IFN-inducible genes resulting in the establishment of an antimicrobial environment. However, the regulatory mechanisms underlying the signaling pathways responsible for the induction of innate immune responses by dsDNA are still not fully understood. Recently, we showed that the translocation and subsequent assembly of the multispanning membrane protein, stimulator of interferon genes (STING), is critical for dsDNA-triggered innate immune responses. Following stimulation by dsDNA, STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus where it associates with TANK-binding kinase 1 (TBK1) on cytoplasmic punctate structures to induce the interferon regulatory factor 3 (IRF3)-dependent transcription of type I IFNs and IFN-inducible genes. We have also shown that dsDNA stimulation induces the colocalization of STING with the autophagy-related proteins Atg9a and microtubule-associated protein 1 light chain 3 (LC3). The targeted disruption of Atg9a, a multispanning membrane protein essential for autophagy, greatly promotes the dsDNA-driven assembly of STING and TBK1 leading to the aberrant activation of the innate immune response. However, the loss of Atg7, another essential component for autophagosome formation, does not affect the dsDNA-stimulated translocation of STING. Hence, Atg9a is a regulator of STING-mediated innate immune response as well as an essential autophagy protein. These findings indicate that dynamic membrane trafficking is triggered by dsDNA stimulation and plays a pivotal role in the signal transduction required for optimal activation of the innate immune response.
Saitoh
Tatsuya
T
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Fujita
Naonobu
N
Yoshimori
Tamotsu
T
Akira
Shizuo
S
D000818:Animals; D000071183:Autophagy-Related Proteins; D004247:DNA / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D007372:Interferons / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D033921:Vesicular Transport Proteins; D000099197:STING Protein
D000071183:Autophagy-Related Proteins; D004247:DNA; D007372:Interferons; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C549015:Atg9A protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein