Gcn5 and PCAF negatively regulate interferon‐β production through HAT ‐independent inhibition of TBK 1

Abstract

Viral infection triggers innate immune signaling, which in turn induces interferon‐β ( IFN ‐β) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase ( HAT ) with partial functional redundancy with PCAF (Kat2b), and Gcn5/ PCAF ‐mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/ PCAF and H3K9ac regulate IFN ‐β production is unknown. Here, we show that Gcn5/ PCAF ‐mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/ PCAF repress IFN ‐β production and innate antiviral immunity in several cell types in a HAT ‐independent and non‐transcriptional manner: by inhibiting the innate immune signaling kinase TBK 1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN ‐β production and innate immune signaling. image This study shows that, contrary to the current model and despite their recruitment to the IFN B promoter, Gcn5 and PCAF negatively regulate IFN ‐β production. They do so in a histone acetyltransferase‐independent manner, through the inhibition of TBK 1. Gcn5/ PCAF and Gcn5/ PCAF ‐mediated H 3 K 9ac are largely dispensable for gene activation in fibroblasts. Gcn5/PCAF repress IFNB production and innate immunity independent of HAT activity. Gcn5 inhibits phosphorylation and activation of innate immune signaling kinase TBK 1.