Murine cytomegalovirus IE3-dependent transcription is required for DAI/ZBP1-mediated necroptosis
- EMBO Rep. 2017 Aug;18(8):1429-1441. doi: 10.15252/embr.201743947.
- 1. Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
- 2. Department of Microbiology, Immunology & Molecular Genetics, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA.
- 3. Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA [email protected].
DNA-dependent activator of interferon regulatory factors/Z-DNA binding protein 1 (DAI/ZBP1) 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 IE3-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/ZBP1, Zα2, is required to sense virus and trigger Necroptosis. Thus, MCMV IE3-dependent transcription from the viral genome plays a crucial role in activating DAI/ZBP1-dependent Necroptosis. This implicates RNA transcripts generated by a large double-stranded DNA virus as a biologically relevant ligand for DAI/ZBP1 during natural viral Infection.