Murine cytomegalovirus IE 3‐dependent transcription is required for DAI / ZBP 1‐mediated necroptosis

Abstract

DNA ‐dependent activator of interferon regulatory factors/Z‐ DNA binding protein 1 ( DAI / ZBP 1) is a crucial sensor of necroptotic cell death induced by murine cytomegalovirus ( MCMV ) in its natural host. Here, we show that viral capsid transport to the nucleus and subsequent viral IE 3‐dependent early transcription are required for necroptosis. Necroptosis induction does not depend on input virion DNA or newly synthesized viral DNA . A putative RNA ‐binding domain of DAI / ZBP 1, Zα2, is required to sense virus and trigger necroptosis. Thus, MCMV IE 3‐dependent transcription from the viral genome plays a crucial role in activating DAI / ZBP 1‐dependent necroptosis. This implicates RNA transcripts generated by a large double‐stranded DNA virus as a biologically relevant ligand for DAI / ZBP 1 during natural viral infection. image DAI / ZBP 1‐mediated necroptosis triggered by cytomegalovirus infection requires nascent transcription mediated by the viral transactivator IE 3. The Z‐ RNA binding domain of DAI is critical for this, suggesting that DAI acts as an RNA sensor of DNA virus infection. MCMV ‐induced necroptosis requires nuclear capsid transport, but not viral replication. Early IE 3‐dependent transcription after MCMV infection is required for necroptosis. The Zα2 and RHIM ‐A domains of DAI are essential for virus‐induced necroptosis.