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Manipulation of apoptosis and necroptosis signaling by herpesviruses

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Abstract

Like apoptosis, necroptosis is an innate immune mechanism that eliminates pathogen-infected cells. Receptor-interacting protein kinase (RIP)3 (also called RIPK3) mediates necrotic death by phosphorylating an executioner protein, MLKL, leading to plasma membrane leakage. The pathway is triggered against viruses that block caspase 8. In murine CMV, the viral inhibitor of caspase 8 activation prevents extrinsic apoptosis but also has the potential to unleash necroptosis. This virus encodes the viral inhibitor of RIP activation to prevent RIP homotypic interaction motif (RHIM)-dependent signal transduction and necroptosis. Recent investigations reveal a similar mechanism at play in the human alpha-herpesviruses, herpes simplex virus (HSV)1 and HSV2, where RHIM competitor function and caspase 8 suppression are carried out by the virus-encoded large subunit of ribonucleotide reductase (R1). In human cells, R1 inhibition of caspase 8 prevents TNF-induced apoptosis, but sensitizes to TNF-induced necroptosis. The RHIM and caspase 8 interaction domains of R1 collaborate to prevent RIP3-dependent steps and enable both herpesviruses to deflect host cell death machinery that would cut short infection. In mouse cells, HSV1 infection by itself triggers necroptosis by driving RIP3 protein kinase activity. HSV1 R1 contributes to the activation of RIP3 adaptor function in mice, a popular host animal for experimental infection. Based on these studies, infection of RIP3-kinase inactive mice should be explored in models of pathogenesis and latency. The necrotic death pathway that is suppressed during infection in the natural host becomes a cross-species barrier to infection in a non-natural host.

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Acknowledgments

Support was from NIH (PHS Grants R01 AI020211 and R01 GM112547 to E.S.M and DP1 OD012198 to W.J.K.), although the content is solely the responsibility of the authors and not the NIH or PHS.

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This manuscript represents the effort of the authors such that all data are original, and the ideas presented are the authors’ own. All co-authors have consented to submission and have contributed sufficiently to the scientific work and therefore share collective responsibility for the results.

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  1. Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Hongyan Guo, William J. Kaiser & Edward S. Mocarski

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  1. Hongyan Guo
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  2. William J. Kaiser
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  3. Edward S. Mocarski
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Correspondence to Edward S. Mocarski.

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This article is part of the Special Issue on Cytomegalovirus.

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Guo, H., Kaiser, W.J. & Mocarski, E.S. Manipulation of apoptosis and necroptosis signaling by herpesviruses. Med Microbiol Immunol 204, 439–448 (2015). https://doi.org/10.1007/s00430-015-0410-5

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  • DOI: https://doi.org/10.1007/s00430-015-0410-5

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