title: 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.
authors.affiliation: Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
authors.forename: Florent
authors.initials: F
authors.lastname: Dufour
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.forename: Angela
authors.initials: A
authors.lastname: Pearson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
authors.forename: Yves
authors.initials: Y
authors.lastname: Langelier
mesh_terms: D017209:Apoptosis; D061945:Caspase Inhibitors; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D018258:Herpesvirus 2, Human / Q000201:enzymology*; D006801:Humans; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors; D011070:Poly I-C / Q000633:toxicity*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D012264:Ribonucleotide Reductases / Q000378:metabolism*
chemical_list: C119724:AGFG1 protein, human; D061945:Caspase Inhibitors; D028861:Nuclear Pore Complex Proteins; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D012264:Ribonucleotide Reductases; D011070:Poly I-C