Abstract
We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha- (TNFα) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellular-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-κB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein–Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6∆ showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.
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References
Wong GH, Tartaglia LA, Lee MS, Goeddel DV (1992) Antiviral activity of tumor necrosis factor is signaled through the 55-kDa type I TNF receptor [corrected]. J Immunol 149:3350–3353
Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, Borden EC (2003) Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 8:237–249
Ishikawa T, Yamada H, Oyamada A, Goshima F, Nishiyama Y, Yoshikai Y (2009) Protective role of Fas-FasL signaling in lethal infection with herpes simplex virus type 2 in mice. J Virol 83:11777–11783
Lokensgard JR, Hu S, Sheng W, van Oijen M, Cox D, Cheeran MC, Peterson PK (2001) Robust expression of TNF-alpha, IL-1beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neurovirol 7:208–219
Chen SH, Oakes JE, Lausch RN (1994) Synergistic anti-herpes effect of TNF-alpha and IFN-gamma in human corneal epithelial cells compared with that in corneal fibroblasts. Antiviral Res 25:201–213
Sergerie Y, Rivest S, Boivin G (2007) Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis. J Infect Dis 196:853–860
Langelier Y, Bergeron S, Chabaud S, Lippens J, Guilbault C, Sasseville AM, Denis S, Mosser DD, Massie B (2002) The R1 subunit of herpes simplex virus ribonucleotide reductase protects cells against apoptosis at, or upstream of, caspase-8 activation. J Gen Virol 83:2779–2789
Liang L, Roizman B (2006) Herpes simplex virus 1 precludes replenishment of the short-lived receptor of tumor necrosis factor alpha by virion host shutoff-dependent degradation of its mRNA. J Virol 80:7756–7759
Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355
Kreuz S, Siegmund D, Scheurich P, Wajant H (2001) NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 21:3964–3973
Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S (2001) Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem 276:20633–20640
Bagneris C, Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C, Waksman G, Barrett T (2008) Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell 30:620–631
Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190
Harper N, Hughes M, MacFarlane M, Cohen GM (2003) Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biol Chem 278:25534–25541
Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16:139–144
Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65
Muppidi JR, Tschopp J, Siegel RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21:461–465
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683
Goldstein DJ, Weller SK (1988) Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant. Virology 166:41–51
Ingemarson R, Lankinen H (1987) The herpes simplex virus type 1 ribonucleotide reductase is a tight complex of the type alpha 2 beta 2 composed of 40 K and 140 K proteins, of which the latter shows multiple forms due to proteolysis. Virology 156:417–422
Swain MA, Galloway DA (1986) Herpes simplex virus specifies two subunits of ribonucleotide reductase encoded by 3′-coterminal transcripts. J Virol 57:802–808
Perkins D, Pereira EF, Gober M, Yarowsky PJ, Aurelian L (2002) The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) blocks apoptosis in hippocampal neurons, involving activation of the MEK/MAPK survival pathway. J Virol 76:1435–1449
Conner J (1999) The unique N terminus of herpes simplex virus type 1 ribonucleotide reductase large subunit is phosphorylated by casein kinase 2, which may have a homologue in Escherichia coli. J Gen Virol 80(Pt 6):1471–1476
Langelier Y, Champoux L, Hamel M, Guilbault C, Lamarche N, Gaudreau P, Massie B (1998) The R1 subunit of herpes simplex virus ribonucleotide reductase is a good substrate for host cell protein kinases but is not itself a protein kinase. J Biol Chem 273:1435–1443
Gober MD, Wales SQ, Aurelian L (2005) Herpes simplex virus type 2 encodes a heat shock protein homologue with apoptosis regulatory functions. Front Biosci 10:2788–2803
Chabaud S, Lambert H, Sasseville AM, Lavoie H, Guilbault C, Massie B, Landry J, Langelier Y (2003) The R1 subunit of herpes simplex virus ribonucleotide reductase has chaperone-like activity similar to Hsp27. FEBS Lett 545:213–218
Walsh D, Mohr I (2006) Assembly of an active translation initiation factor complex by a viral protein. Genes Dev 20:461–472
Chabaud S, Sasseville AM, Elahi SM, Caron A, Dufour F, Massie B, Langelier Y (2007) The ribonucleotide reductase domain of the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase is essential for R1 antiapoptotic function. J Gen Virol 88:384–394
Whitehurst CB, Ning S, Bentz GL, Dufour F, Gershburg E, Shackelford J, Langelier Y, Pagano JS (2009) The EBV deubiquitinating enzyme, BPLF1, reduces EBV ribonucleotide reductase activity. J Virol 83:4345–4353
Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, Cohen J, Lenardo MJ (1998) Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141:1243–1253
Laramee M, Chabot C, Cloutier M, Stenne R, Holgado-Madruga M, Wong AJ, Royal I (2007) The scaffolding adapter Gab1 mediates vascular endothelial growth factor signaling and is required for endothelial cell migration and capillary formation. J Biol Chem 282:7758–7769
Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, Tinel A, Deperthes D, Calderara S, Schulthess T, Engel J, Schneider P, Tschopp J (2003) Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol 23:1428–1440
Scaffidi C, Medema JP, Krammer PH, Peter ME (1997) FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biol Chem 272:26953–26958
Nie Z, Phenix BN, Lum JJ, Alam A, Lynch DH, Beckett B, Krammer PH, Sekaly RP, Badley AD (2002) HIV-1 protease processes procaspase 8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation. Cell Death Differ 9:1172–1184
Medema JP, Scaffidi C, Krammer PH, Peter ME (1998) Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex. J Biol Chem 273:3388–3393
Peant B, Diallo JS, Dufour F, Le Page C, Delvoye N, Saad F, Mes-Masson AM (2009) Over-expression of IkappaB-kinase-epsilon (IKKepsilon/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell lines. Prostate 69:706–718
Lamarche N, Matton G, Massie B, Fontecave M, Atta M, Dumas F, Gaudreau P, Langelier Y (1996) Production of the R2 subunit of ribonucleotide reductase from herpes simplex virus with prokaryotic and eukaryotic expression systems: higher activity of R2 produced by eukaryotic cells related to higher iron-binding capacity. Biochem J 320(Pt 1):129–135
Cohen EA, Gaudreau P, Brazeau P, Langelier Y (1986) Neutralization of herpes simplex virus ribonucleotide reductase activity by an oligopeptide-induced antiserum directed against subunit H2. J Virol 60:1130–1133
Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869
Osaki M, Oshimura M, Ito H (2004) PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9:667–676
Dida F, Li Y, Iwao A, Deguchi T, Azuma E, Komada Y (2008) Resistance to TRAIL-induced apoptosis caused by constitutional phosphorylation of Akt and PTEN in acute lymphoblastic leukemia cells. Exp Hematol 36:1343–1353
Pucci B, Indelicato M, Paradisi V, Reali V, Pellegrini L, Aventaggiato M, Karpinich NO, Fini M, Russo MA, Farber JL, Tafani M (2009) ERK-1 MAP kinase prevents TNF-induced apoptosis through Bad phosphorylation and inhibition of Bax translocation in HeLa Cells. J Cell Biochem 108:1166–1174
Hunter JC, Smith CC, Bose D, Kulka M, Broderick R, Aurelian L (1995) Intracellular internalization and signaling pathways triggered by the large subunit of HSV-2 ribonucleotide reductase (ICP10). Virology 210:345–360
Luschen S, Falk M, Scherer G, Ussat S, Paulsen M, Adam-Klages S (2005) The Fas-associated death domain protein/caspase-8/c-FLIP signaling pathway is involved in TNF-induced activation of ERK. Exp Cell Res 310:33–42
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489–27494
Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–5248
Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15:36–42
Hay S, Kannourakis G (2002) A time to kill: viral manipulation of the cell death program. J Gen Virol 83:1547–1564
Bertin J, Armstrong RC, Ottilie S, Martin DA, Wang Y, Banks S, Wang GH, Senkevich TG, Alnemri ES, Moss B, Lenardo MJ, Tomaselli KJ, Cohen JI (1997) Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA 94:1172–1176
Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS (2001) A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci USA 98:7829–7834
Fernandes-Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci USA 93:7464–7469
Chen M, Orozco A, Spencer DM, Wang J (2002) Activation of initiator caspases through a stable dimeric intermediate. J Biol Chem 277:50761–50767
Iordanov MS, Ryabinina OP, Schneider P, Magun BE (2005) Two mechanisms of caspase 9 processing in double-stranded RNA- and virus-triggered apoptosis. Apoptosis 10:153–166
Neznanov N, Chumakov KP, Ullrich A, Agol VI, Gudkov AV (2002) Unstable receptors disappear from cell surface during poliovirus infection. Med Sci Monit 8:BR391–BR396
Tewari M, Dixit VM (1995) Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem 270:3255–3260
Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521
Saito K, Meyer K, Warner R, Basu A, Ray RB, Ray R (2006) Hepatitis C virus core protein inhibits tumor necrosis factor alpha-mediated apoptosis by a protective effect involving cellular FLICE inhibitory protein. J Virol 80:4372–4379
Goodkin ML, Morton ER, Blaho JA (2004) Herpes simplex virus infection and apoptosis. Int Rev Immunol 23:141–172
Wales SQ, Li B, Laing JM, Aurelian L (2007) The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation. J Neurochem 103:365–379
Hardy S, St-Onge GG, Joly E, Langelier Y, Prentki M (2005) Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem 280:13285–13291
Filippova M, Johnson MM, Bautista M, Filippov V, Fodor N, Tungteakkhun SS, Williams K, Duerksen-Hughes PJ (2007) The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity. J Virol 81:4116–4129
Filippova M, Parkhurst L, Duerksen-Hughes PJ (2004) The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J Biol Chem 279:25729–25744
Chiou SH, Yang YP, Lin JC, Hsu CH, Jhang HC, Yang YT, Lee CH, Ho LL, Hsu WM, Ku HH, Chen SJ, Chen SS, Chang MD, Wu CW, Juan LJ (2006) The immediate early 2 protein of human cytomegalovirus (HCMV) mediates the apoptotic control in HCMV retinitis through up-regulation of the cellular FLICE-inhibitory protein expression. J Immunol 177:6199–6206
Galvan V, Roizman B (1998) Herpes simplex virus 1 induces and blocks apoptosis at multiple steps during infection and protects cells from exogenous inducers in a cell-type-dependent manner. Proc Natl Acad Sci USA 95:3931–3936
McCormick AL, Skaletskaya A, Barry PA, Mocarski ES, Goldmacher VS (2003) Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses. Virology 316:221–233
Keller N, Mares J, Zerbe O, Grutter MG (2009) Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation. Structure 17:438–448
Carrington PE, Sandu C, Wei Y, Hill JM, Morisawa G, Huang T, Gavathiotis E, Wei Y, Werner MH (2006) The structure of FADD and its mode of interaction with procaspase-8. Mol Cell 22:599–610
Lembo D, Brune W (2009) Tinkering with a viral ribonucleotide reductase. Trends Biochem Sci 34:25–32
Galluzzi L, Kepp O, Morselli E, Vitale I, Senovilla L, Pinti M, Zitvogel L, Kroemer G (2010) Viral strategies for the evasion of immunogenic cell death. J Intern Med 267:526–542
Kather A, Raftery MJ, Devi-Rao G, Lippmann J, Giese T, Sandri-Goldin RM, Schonrich G (2010) Herpes simplex virus type 1 (HSV-1)-induced apoptosis in human dendritic cells as a result of downregulation of cellular FLICE-inhibitory protein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequences. J Virol 84:1034–1046
Lundberg P, Welander PV, Edwards CK 3rd, van Rooijen N, Cantin E (2007) Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 81:1451–1460
Acknowledgments
This work was supported by Canadian Institutes of Health Research Grant NRF #67052. We thank Angela Pearson, Andrew D. Badley, Marcus E. Peter and Joseph S. Pagano for their kind gifts of plasmids and antibodies, Sandra Weller for the generous donation of ICP6∆, Pascal Schneider for its kind gift of Fc:FasL, and W. Edward C. Bradley as well as Richard Bertrand for critical manuscript editing. This is National Research Council of Canada publication No. 52767.
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Dufour, F., Sasseville, A.MJ., Chabaud, S. et al. The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8. Apoptosis 16, 256–271 (2011). https://doi.org/10.1007/s10495-010-0560-2
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DOI: https://doi.org/10.1007/s10495-010-0560-2