Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kB activation through TBK1

Takayuki Abe, Glen N Barber

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-kB) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in response to STING activation by double-stranded DNA (dsDNA). Furthermore, TANK-binding kinase 1 (TBK1) associated with STING was found to facilitate dsDNA-mediated canonical activation of NF-kB as well as IRF3 to promote proinflammatory gene transcription. The triggering of NF-kB function was noted to require TRAF6 activation. Our findings detail a novel dsDNA-mediated NF-kB activation pathway facilitated through a STING-TRAF6-TBK1 axis and suggest a target for therapeutic intervention to plausibly stimulate antiviral activity or, alternatively, avert dsDNA-mediated inflammatory disease.

Original languageEnglish
Pages (from-to)5328-5341
Number of pages14
JournalJournal of Virology
Volume88
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

IKappaB kinase
gene induction
interferons
Interferons
Phosphotransferases
Genes
TNF Receptor-Associated Factor 6
Interferon Regulatory Factor-3
genes
DNA
Human herpesvirus 1
Essential Genes
Human Herpesvirus 1
gene activation
Heat-Shock Proteins
Protein Kinases
Transcriptional Activation
Antiviral Agents
lethal genes
mitogen-activated protein kinase

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kB activation through TBK1. / Abe, Takayuki; Barber, Glen N.

In: Journal of Virology, Vol. 88, No. 10, 01.01.2014, p. 5328-5341.

Research output: Contribution to journalArticle

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