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Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

ABSTRACT: The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-?, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.

SUBMITTER: Wang X

PROVIDER: S-EPMC4217423 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

Wang Xing X Li Yun Y Liu Shan S Yu Xiaoliang X Li Lin L Shi Cuilin C He Wenhui W Li Jun J Xu Lei L Hu Zhilin Z Yu Lu L Yang Zhongxu Z Chen Qin Q Ge Lin L Zhang Zili Z Zhou Biqi B Jiang Xuejun X Chen She S He Sudan S

Proceedings of the National Academy of Sciences of the United States of America 20141014 43

The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host- ...[more]

PMID: 25316792

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Project description:Topic: Herpes simplex virus (HSV) and varicella zoster virus (VZV) are the most common ocular pathogens associated with infectious anterior uveitis. Currently, there are a number of antiviral agents administered to treat viral anterior uveitis (VAU). However, there is no consensus or guidelines about the most appropriate approach leading for the best treatment outcomes with fewer ocular complications. Clinical Relevance: To perform a systematic review and meta-analysis of the efficacy of different antiviral therapies in the management of anterior uveitis secondary to HSV and VZV. Methods: We searched PubMed, Web of Science, CINAHL, OVID, and Embase up to January 2020. Randomized trials, non-randomized intervention studies, controlled before and after studies and observational studies assessing the effect of oral and or topical treatments for VAU were considered. Data extraction and analysis with evaluation of the risk of bias in the included trials were performed. Results: Oral acyclovir demonstrated a statistically significant good treatment outcome in the management of VZV anterior uveitis (vs. placebo) (OR 0.26, 95% CI 0.11-0.59), but did not have similar effect in HSV anterior uveitis (OR 0.47, 95% CI 0.15-1.50). In the treatment of VZV anterior uveitis, there was significant superiority of oral acyclovir-7 day course-over topical acyclovir (OR 4.17, 95% CI 1.28-13.52). Whereas, there was no significant superiority of one of the following treatment regimens over the others: topical acyclovir over topical corticosteroids (OR 1.86, 95% CI 0.67-5.17), and oral acyclovir-7 day course-over oral acyclovir-14 day course-(OR 0.21, 95% CI 0.01-4.50) or oral valaciclovir (OR 1.40, 95% CI 0.48-4.07). Conclusion: Treatment of HSV and VZV anterior uveitis is currently based on individual experiences and limited literature, largely due to weak clinical trial evidence in this regard. Our results highlight the existence of a substantial gap in our evidence base. This finding might contribute to future research studies to ascertain the role of different antiviral therapies in the treatment of VAU. Systematic Review Registration: PROSPERO registration number: CRD420202 00404.

Dataset Information

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

Publications

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

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