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Author Notes:

Correspondence: William J. Kaiser; Email- kaiserw@uthscsa.edu

Authors’ contributions: H.G., E.S.M., and W.J.K. designed research; H.G., R.P.G., and A.F. performed research; V.J.L., K.B.R., and J.W.U. contributed new reagents/analytic tools; H.G. analyzed data; H.G. and W.J.K. wrote, and E.S.M. edited the paper

Disclosures: The authors declare that they have no conflict of interest.

Subjects:

Research Funding:

This work was supported by Public Health Service Grants R01 AI020211, R01 AI118853 (to E.S.M.) and DP5OD012198 (to W.J. K.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • MIXED LINEAGE KINASE
  • CELL-DEATH PATHWAYS
  • DNA-DEPENDENT ACTIVATOR
  • IFN-REGULATORY FACTORS
  • NF-KAPPA-B
  • PROGRAMMED NECROSIS
  • DOMAIN-LIKE
  • INNATE IMMUNITY
  • BINDING DOMAIN
  • PROTEIN

Species-independent contribution of ZBP1/DAI/DLM-1-triggered necroptosis in host defense against HSV1

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Journal Title:

Cell Death and Disease

Volume:

Volume 9, Number 8

Publisher:

, Pages 816-816

Type of Work:

Article | Final Publisher PDF

Abstract:

Necroptosis complements apoptosis as a host defense pathway to stop virus infection. Herpes simplex virus shows a propensity to trigger necroptosis of mouse cells and mice even though cell death is blocked in human cells through UL39-encoded ICP6. This ribonucleotide reductase large subunit (R1) nucleates RHIM-dependent oligomerization of RIP3 kinase (RIPK3, also known as RIP3) in mouse cells but inhibits activation in cells from the natural human host. By interrogating the comparative behavior of ICP6-deficient viruses in mouse and human cells, here we unveil virus-induced necroptosis mediated by Z-DNA-binding protein 1 (ZBP1, also known as DAI). ZBP1 acts as a pathogen sensor to detect nascent RNA transcripts rather than input viral DNA or viral DNA generated through replication. Consistent with the implicated role of virus-induced necroptosis in restricting infection, viral pathogenesis is restored in Zbp1−/−, Ripk3−/−and Mlkl−/−mice. Thus, in addition to direct activation of RIPK3 via ICP6, HSV1 infection in mice and mouse cells triggers virus-induced necroptosis through ZBP1. Importantly, virus-induced necroptosis is also induced in human HT-29 cells by ICP6 mutant viruses; however, ZBP1 levels must be elevated for this pathway to be active. Thus, our studies reveal a common, species-independent role of this nucleic acid sensor to detect the presence of this virus. HSV1 ICP6 functions as a bona fide RHIM signaling inhibitor to block virus-induced necroptosis in its natural host. Altogether, ZBP1-dependent restriction of herpesvirus infection emerges as a potent antiviral armament of the innate immune system.

Copyright information:

© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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