title: The R1 subunit of herpes simplex virus ribonucleotide reductase protects cells against apoptosis at, or upstream of, caspase-8 activation.
abstract: The R1 subunit of herpes simplex virus (HSV) ribonucleotide reductase, which in addition to its C-terminal reductase domain possesses a unique N-terminal domain of about 400 amino acids, is thought to have an additional, as yet unknown, function. Here, we report that the full-length HSV-2 R1 has an anti-apoptotic function able to protect cells against death triggered by expression of R1(Delta2-357), an HSV-2 R1 subunit with its first 357 amino acids deleted. We further substantiate the R1 anti-apoptotic activity by showing that its accumulation at low level could completely block apoptosis induced by TNF-receptor family triggering. Activation of caspase-8 induced either by TNF or by Fas ligand expression was prevented by the R1 protein. As HSV R1 did not inhibit cell death mediated by several agents acting via the mitochondrial pathway (Bax overexpression, etoposide, staurosporine and menadione), it is proposed that it functions to interrupt specifically death receptor-mediated signalling at, or upstream of, caspase-8 activation. The N-terminal domain on its own did not exhibit anti-apoptotic activity, suggesting that both domains of R1 or part(s) of them are necessary for this new function. Evidence for the importance of HSV R1 in protecting HSV-infected cells against cytokine-induced apoptosis was obtained with the HSV-1 R1 deletion mutants ICP6Delta and hrR3. These results show that, in addition to its ribonucleotide reductase function, which is essential for virus reactivation, HSV R1 could contribute to virus propagation by preventing apoptosis induced by the immune system.
authors.affiliation: Département de microbiologie et immunologie de l'Université de Montréal, Montréal, Québec, Canada2.|Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Yves
authors.initials: Y
authors.lastname: Langelier
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bergeron
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chabaud
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Julie
authors.initials: J
authors.lastname: Lippens
authors.affiliation: Institut de recherche en biotechnologie, 6100 ave Royalmount, Montréal, CanadaH4P 2R23.|Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Claire
authors.initials: C
authors.lastname: Guilbault
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: A Marie-Josée
authors.initials: AM
authors.lastname: Sasseville
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, Québec, CanadaH2L 4M11.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Denis
authors.affiliation: Institut de recherche en biotechnologie, 6100 ave Royalmount, Montréal, CanadaH4P 2R23.
authors.forename: Dick D
authors.initials: DD
authors.lastname: Mosser
authors.affiliation: INRS-IAF Université du Québec, Laval, Québec, CanadaH7N 4Z34.|Institut de recherche en biotechnologie, 6100 ave Royalmount, Montréal, CanadaH4P 2R23.|Département de microbiologie et immunologie de l'Université de Montréal, Montréal, Québec, Canada2.
authors.forename: Bernard
authors.initials: B
authors.lastname: Massie
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006367:HeLa Cells; D018258:Herpesvirus 2, Human / Q000201:enzymology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017500:Adenovirus E1A Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C100671:ICP10 protein, herpes simplex virus type 2; D012264:Ribonucleotide Reductases; D017346:Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases