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

Haripriya Sridharan; Katherine B. Ragan; Hongyan Guo; Ryan P. Gilley; Vanessa J. Landsteiner; William J. Kaiser; Jason W. Upton

doi:10.15252/embr.201743947

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

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

Microbiology, Immunology & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1429-1441
Number of pages	13
Journal	EMBO Reports
Volume	18
Issue number	8
DOIs	https://doi.org/10.15252/embr.201743947
State	Published - Aug 2017

Keywords

DAI/ZBP1
IE3
RIPK3
murine cytomegalovirus
necroptosis

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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@article{8508c41c2ec145bdafbe6a2225a7f8b8,

title = "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, 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",

author = "Haripriya Sridharan and Ragan, {Katherine B.} and Hongyan Guo and Gilley, {Ryan P.} and Landsteiner, {Vanessa J.} and Kaiser, {William J.} and Upton, {Jason W.}",

note = "Funding Information: The authors thank Chris Sullivan, Bryan Davies, Ed Mocarski, Siddharth Balachandran, Jan Rehwinkel, and Jonathan Maelfait for insightful discussions, and Tillman Burckstummer and Giulio Superti-Furga (CeMM) for reagents. Work was supported by National Institutes of Health Public Service Grant DP1 OD012198 to W.J.K., and Cancer Prevention & Research Institute of Texas (CPRIT) Scholar Award (R1202) and the William and Ella Owens Medical Research Foundation (201402505-001) to J.W.U. Publisher Copyright: {\textcopyright} 2017 The Authors",

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doi = "10.15252/embr.201743947",

language = "English (US)",

volume = "18",

pages = "1429--1441",

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AU - Sridharan, Haripriya

AU - Ragan, Katherine B.

AU - Guo, Hongyan

AU - Gilley, Ryan P.

AU - Landsteiner, Vanessa J.

AU - Kaiser, William J.

AU - Upton, Jason W.

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PY - 2017/8

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N2 - 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.

AB - 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.

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

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