DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF‐κB

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Abstract
Detection of viral nucleic acids is central to antiviral immunity. Recently, DAI/ZBP1 (DNA‐dependent activator of IRFs/Z‐DNA binding protein 1) was identified as a cytoplasmic DNA sensor and shown to activate the interferon regulatory factor (IRF) and nuclear factor‐kappa B (NF‐κB) transcription factors, leading to type‐I interferon production. DAI‐induced IRF activation depends on TANK‐binding kinase 1 (TBK1), whereas signalling pathways and molecular components involved in NF‐κB activation remain elusive. Here, we report the identification of two receptor‐interacting protein (RIP) homotypic interaction motifs (RHIMs) in the DAI protein sequence, and show that these domains relay DAI‐induced NF‐κB signals through the recruitment of the RHIM‐containing kinases RIP1 and RIP3. We show that knockdown of not only RIP1, but also RIP3 affects DAI‐induced NF‐κB activation. Importantly, RIP recruitment to DAI is inhibited by the RHIM‐containing murine cytomegalovirus (MCMV) protein M45. These findings delineate the DAI signalling pathway to NF‐κB and suggest a possible new immune modulation strategy of the MCMV.