title: The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms.
abstract: The effect of the human papillomavirus type 16 (HPV-16) E5 protein on apoptosis was investigated by using the polyclonal HaCaT-cell lines stably transfected either with E5 (HaCaT/E5) or the empty vector (HaCaT/pMSG) as reference. Apoptosis was triggered either by Fas ligand (FasL) or by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and was monitored by detection of cleavage of procaspase-8 and procaspase-3, as well as their substrate poly(ADP-ribose) polymerase (PARP). In contrast to the HaCaT/pMSG control cells we found that apoptosis induced by either of the two ligands is strongly suppressed in the E5-expressing keratinocytes. Fas expression is reduced by about a factor of two in HaCaT/E5 cells, which could be part of the mechanisms that protect the cells from FasL-induced apoptosis. For the TRAIL receptors, no such downregulation was observed. Here, E5 impairs the formation of the death-inducing signaling complex triggered by TRAIL. Apparently, E5 employs different mechanisms to inhibit death receptor signaling. This effect is not restricted to HaCaT/E5 cells since we found that the mouse fibroblast cell line A31-E5 is protected from TRAIL-induced apoptosis, as well but not the E5-lacking control cells A31-Neo. However, no such protection was observed upon FasL-induced apoptosis. Presumably, some of the antiapoptotic mechanisms employed by E5 of the human pathogenic HPV-16 are cell type specific. We propose that inhibition of ligand-mediated apoptosis in human keratinocytes is a primary function of the HPV-16 E5 protein needed to prevent apoptosis at early stages of viral infection.
authors.affiliation: Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany. k.kabsch@dkfz-heidelberg.de
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kabsch
authors.forename: Angel
authors.initials: A
authors.lastname: Alonso
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004792:Enzyme Precursors / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004792:Enzyme Precursors; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D011065:Poly(ADP-ribose) Polymerases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse