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.

Haripriya Sridharan ¹, Katherine B Ragan ¹, Hongyan Guo ², Ryan P Gilley ², Vanessa J Landsteiner ¹, William J Kaiser ², Jason W Upton ³

Affiliations

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 upton@austin.utexas.edu.

PMID: 28607035 DOI: 10.15252/embr.201743947

Abstract

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.

Keywords

DAI/ZBP1; IE3; RIPK3; murine cytomegalovirus; necroptosis.

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