DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response (P1375)

TLDR: In this article, the authors identify the helicase, DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) as the pattern recognition receptor (PRR) that senses both cyclic-di-GMP and cyclic -di-AMP.

Abstract: Cytosolic detection of bacterially derived secondary messengers cyclic-di-GMP (c-di-GMP) or cyclic -di-AMP (c-di-AMP) by the host immune system activates an innate immune response characterized by the induction of type I interferons (IFNs) Induction of IFN by c-di-GMP or c-di-AMP has been shown to be dependent on a stimulator of IFN genes-TANK binding kinase 1-IFN regulatory factor 3 (STING-TBK1-IRF3) signaling axis Although STING has been shown to interact with c-di-GMP, an upstream sensor of these cyclic dinucleotides is unknown Here we identify the helicase, DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) as the pattern recognition receptor (PRR) that senses both c-di-GMP and c-di-AMP DDX41 specifically and directly interacts with c-di-GMP Knockdown of DDX41 via shRNA in murine or human immune cells inhibits the induction of innate immune genes and results in defective STING, TBK1 and IRF3 activation in response to c-di-GMP or c-di-AMP Our findings suggest a mechanism whereby c-di-GMP and c-di-AMP molecules are detected by the DDX41 PRR, which complexes with the STING adaptor to signal to TBK1-IRF3 and activate the IFN response