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GCN5 Negatively Regulates Innate Immune Signaling by Targeting TBK1 Kinase

Thursday, October 11, 2012 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center, Building 45




  • Q. Jin
  • C. Wang
  • L. Yu
  • D. Brian
  • Z. Wang
  • S. Grullon
  • Z. Zhang
  • K. Zhao
  • W. Pemg
  • S. Y. Dent
  • K. Ge


Innate immune signaling leads to phosphorylation and activation of TANK-binding kinase 1 (TBK1), which induces type-I interferon (IFN) production to establish innate immunity against virus infection. However, the mechanism that negatively regulates TBK1 phosphorylation and activation remains poorly understood. Histone acetyltransferase (HAT) GCN5 and GCN5-mediated histone H3K9ac are enriched on active type-I IFN gene promoters, but their roles in regulating production of endogenous type-I IFNs in cells are unclear. Here we show GCN5-mediated H3K9ac correlates well with, but is surprisingly dispensable for, expression of type-I IFN genes and the vast majority of active genes in cells. Strikingly, in a HAT activity-independent manner, GCN5 represses type-I IFN production and innate antiviral immunity in cells. By knocking down individual components of the innate immune signaling in GCN5 KO cells, we find that GCN5 negatively regulates innate immune signaling by targeting TBK1 kinase. Mechanistically, GCN5 prefers to bind phosphorylated active TBK1, and recruits serine/threonine phosphatases PPM1A/PPM1B to dephosphorylate and inactivate the innate immune signaling kinase TBK1. These results identify a HAT activity-independent function of GCN5 as a negative regulator of innate immune signaling and type-I IFN production.

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