The ribonucleotide reductase R1 subunits of herpes simplex virus 1 and 2 protect cells against poly(I * C)-induced apoptosis.

Abstract : We recently provided evidence that the ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 (HSV-1 and -2) protect cells against tumor necrosis factor alpha- and Fas ligand-induced apoptosis by interacting with caspase 8. Double-stranded RNA (dsRNA) is a viral intermediate known to initiate innate antiviral responses. Poly(I * C), a synthetic analogue of viral dsRNA, rapidly triggers caspase 8 activation and apoptosis in HeLa cells. Here, we report that HeLa cells after HSV-1 and HSV-2 infection were quickly protected from apoptosis caused by either extracellular poly(I * C) combined with cycloheximide or transfected poly(I * C). Cells infected with the HSV-1 R1 deletion mutant ICP6Δ were killed by poly(I * C), indicating that HSV-1 R1 plays a key role in antiapoptotic responses to poly(I * C). Individually expressed HSV R1s counteracted caspase 8 activation by poly(I * C). In addition to their binding to caspase 8, HSV R1s also interacted constitutively with receptor-interacting protein 1 (RIP1) when expressed either individually or with other viral proteins during HSV infection. R1(1-834)-green fluorescent protein (GFP), an HSV-2 R1 deletion mutant protein devoid of antiapoptotic activity, did not interact with caspase 8 and RIP1, suggesting that these interactions are required for protection against poly(I * C). HSV-2 R1 inhibited the interaction between the Toll/interleukin-1 receptor domain-containing adaptor-inducing beta interferon (IFN-β) (TRIF) and RIP1, an interaction that is essential for apoptosis triggered by extracellular poly(I * C) plus cycloheximide or TRIF overexpression. TRIF silencing reduced poly(I * C)-triggered caspase 8 activation in mock- and ICP6Δ-infected cells, confirming that TRIF is involved in poly(I * C)-induced apoptosis. Thus, by interacting with caspase 8 and RIP1, HSV R1s impair the apoptotic host defense mechanism prompted by dsRNA.
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Submitted on : Monday, August 6, 2012 - 4:45:28 PM
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Florent Dufour, Luc Bertrand, Angela Pearson, Nathalie Grandvaux, Yves Langelier. The ribonucleotide reductase R1 subunits of herpes simplex virus 1 and 2 protect cells against poly(I * C)-induced apoptosis.. Journal of Virology, American Society for Microbiology, 2011, 85 (17), pp.8689-701. ⟨10.1128/JVI.00362-11⟩. ⟨pasteur-00722936⟩

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