title: Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding Kinase 1 (TBK1) to Restrain STAT3 Activity.
abstract: Cytosolic DNA can elicit beneficial as well as undesirable immune responses. For example, viral or microbial DNA triggers cell-intrinsic immune responses to defend against infections, whereas aberrant cytosolic accumulation of self-DNA results in pathological conditions, such as autoimmunity. Given the importance of these DNA-provoked responses, a better understanding of their molecular mechanisms is needed. Cytosolic DNA engages stimulator of interferon genes (STING) to activate TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor interferon regulatory factor 3 (IRF3) to promote interferon expression. Recent studies have reported that additional transcription factors, including nuclear factor κB (NF-κB) and signal transducer and activator of transcription 6 (STAT6), are also activated by cytosolic DNA, suggesting that cytosolic DNA-induced gene expression is orchestrated by multiple factors. Here we show that cytosolic DNA activates STAT3, another member of the STAT family, via an autocrine mechanism involving interferon β (IFNβ) and IL-6. Additionally, we observed a novel cytosolic DNA-induced phosphorylation at serine 754 in the transactivation domain of STAT3. Upon cytosolic DNA stimulation, Ser754is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser754phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolic DNA. Taken together, our results suggest that cytosolic DNA-induced STAT3 activation via IFNβ and IL-6 is restrained by Ser754phosphorylation of STAT3. Our findings reveal a new signaling axis downstream of the cytosolic DNA pathway and suggest potential interactions between innate immune responses and STAT3-driven oncogenic pathways.
authors.affiliation: From the Department of Cell Biology and Physiology and.|the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Hung-Ching
authors.initials: HC
authors.lastname: Hsia
authors.affiliation: the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Hutti
authors.affiliation: From the Department of Cell Biology and Physiology and albert_baldwin@med.unc.edu.|the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D019898:Autocrine Communication; D002460:Cell Line; D004247:DNA / Q000276:immunology* / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta; D015850:Interleukin-6; D008565:Membrane Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D004247:DNA; D016899:Interferon-beta; D015850:Interleukin-6; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human
keywords: Cytosolic DNA; STAT transcription factor; STAT3; STING; TBK1; cell signaling; innate immunity; phosphorylation