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10.1074/jbc.M116.771964

http://scihub22266oqcxt.onion/10.1074/jbc.M116.771964
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suck abstract from ncbi


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pmid28188292
      J+Biol+Chem 2017 ; 292 (13 ): 5405-5417
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  • Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding Kinase 1 (TBK1) to Restrain STAT3 Activity #MMPMID28188292
  • Hsia HC ; Hutti JE ; Baldwin AS
  • J Biol Chem 2017[Mar]; 292 (13 ): 5405-5417 PMID28188292 show ga
  • 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 ?B (NF-?B) 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 ? (IFN?) 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, Ser(754) is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser(754) phosphorylation 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 IFN? and IL-6 is restrained by Ser(754) phosphorylation 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.
  • |*Signal Transduction [MESH]
  • |Autocrine Communication [MESH]
  • |Cell Line [MESH]
  • |DNA/*immunology/physiology [MESH]
  • |Gene Expression Regulation/immunology [MESH]
  • |Humans [MESH]
  • |Immunity, Innate [MESH]
  • |Interferon-beta [MESH]
  • |Interleukin-6 [MESH]
  • |Membrane Proteins/metabolism [MESH]
  • |Phosphorylation [MESH]
  • |Protein Serine-Threonine Kinases/*metabolism [MESH]


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