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Murine cytomegalovirus IE3-dependent transcription is required for DAI/ZBP1-mediated necroptosis.

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, Z?2, 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.

SUBMITTER: Sridharan H

PROVIDER: S-EPMC5538628 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Murine cytomegalovirus IE3-dependent transcription is required for DAI/ZBP1-mediated necroptosis.

Sridharan Haripriya H Ragan Katherine B KB Guo Hongyan H Gilley Ryan P RP Landsteiner Vanessa J VJ Kaiser William J WJ Upton Jason W JW

EMBO reports 20170612 8

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 ...[more]

PMID: 28607035

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Project description:Ionizing radiation promotes cytosolic DNA sensing and consequent antitumor immune responses. But how tumor cell-intrinsic cytosolic DNA sensing is initiated by radiation remains poorly defined. Here, we demonstrated that STING-mediated type I interferon production in tumor cells after radiation relied on the engagement of MLKL-mediated necroptosis, which was elicited by the ZBP1-RIPK3 signaling axis. Physiologically, tumor cell-intrinsic ZBP1-MLKL cascade augmented antitumor immune responses after radiation largely by regulating STING signaling. Mechanistically, ZBP1-MLKL-dependent necroptosis maintained the enrichment of mitochondria DNA inside the cytosol of tumor cells after radiation in a cell-density dependent fashion, contributing to type I interferon responses. In contrast, ablation of caspase-8 unleashed ZBP1-MLKL cascade to gain enhanced cytosolic DNA sensing, and in turn potentiated therapeutic effects of radiation. Thus, our findings uncover an unanticipated mechanism that ZBP1-MLKL-dependent necroptosis drives cytosolic DNA sensing-mediated antitumor immunity after radiation, and provide new strategy to improve radiotherapy by inhibiting caspase-8 cascade.

2021-10-13 | GSE168016 | GEO

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