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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.