Cytosolic DNA promotes signal transducer and activator of transcription 3 (STAT3) phosphorylation by TANK-binding kinase 1 (TBK1) to restrain STAT3 activity

Hung Ching Hsia, Jessica E. Hutti, Albert S. Baldwin

Research output: Research - peer-reviewArticle

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 DNAactivates 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.UponcytosolicDNAstimulation, Ser754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolicDNA.Taken together, our results suggest that cytosolic DNA-induced STAT3activation via IFNβ and IL-6 is restrained by Ser754 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.

LanguageEnglish (US)
Pages5405-5417
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number13
DOIs
StatePublished - Mar 31 2017

Fingerprint

STAT3 Transcription Factor
Phosphotransferases
Phosphorylation
DNA
Interferons
Genes
Interferon-beta
Interleukin-6
Transcription Factors
STAT6 Transcription Factor
Interferon Regulatory Factor-3
Autoimmunity
Innate Immunity
Serine
Transcriptional Activation
Gene Expression
Infection
Gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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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 DNAactivates 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.UponcytosolicDNAstimulation, Ser754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolicDNA.Taken together, our results suggest that cytosolic DNA-induced STAT3activation via IFNβ and IL-6 is restrained by Ser754 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.",
author = "Hsia, {Hung Ching} and Hutti, {Jessica E.} and Baldwin, {Albert S.}",
year = "2017",
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journal = "Journal of Biological Chemistry",
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T1 - Cytosolic DNA promotes signal transducer and activator of transcription 3 (STAT3) phosphorylation by TANK-binding kinase 1 (TBK1) to restrain STAT3 activity

AU - Hsia,Hung Ching

AU - Hutti,Jessica E.

AU - Baldwin,Albert S.

PY - 2017/3/31

Y1 - 2017/3/31

N2 - 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 DNAactivates 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.UponcytosolicDNAstimulation, Ser754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolicDNA.Taken together, our results suggest that cytosolic DNA-induced STAT3activation via IFNβ and IL-6 is restrained by Ser754 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.

AB - 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 DNAactivates 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.UponcytosolicDNAstimulation, Ser754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolicDNA.Taken together, our results suggest that cytosolic DNA-induced STAT3activation via IFNβ and IL-6 is restrained by Ser754 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.

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