title: The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity.
abstract: Human papillomavirus type 16 (HPV-16) has developed numerous ways to modulate host-initiated immune mechanisms. The HPV-16 E6 oncoprotein, for example, can modulate the cellular level, and consequently the activity, of procaspase 8, thus modifying the cellular response to cytokines of the tumor necrosis factor family. E6 from HPV-16, but not E6 from the low-risk types 6b and 11, alters the cellular level of procaspase 8 in a dose-dependent manner. Both the large and small (E6*) isoforms of E6, which originate by way of alternate splicing, can modulate procaspase 8 stability. Intriguingly, although both isoforms bind to procaspase 8, the large isoform accelerates the degradation of procaspase 8 while the small isoform stabilizes it. Binding leads to a change in the ability of procaspase 8 to bind either to itself or to FADD (Fas-associated death domain), with the large version of E6 able to inhibit this binding while the small isoform does not. Consistent with this model, knockdown of the large version of E6 by small interfering RNA leads to increases in the levels of procaspase 8 and its binding to both itself and FADD. Thus, these alternatively spliced isoforms can modulate both the level and the activity of procaspase 8 in opposite directions.
authors.affiliation: Department of Biochemistry and Microbiology, 11085 Campus Street, 121 Mortensen Hall, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Filippova
authors.forename: Melyssa M
authors.initials: MM
authors.lastname: Johnson
authors.forename: Marnelli
authors.initials: M
authors.lastname: Bautista
authors.forename: Valery
authors.initials: V
authors.lastname: Filippov
authors.forename: Nadja
authors.initials: N
authors.lastname: Fodor
authors.forename: Sandy S
authors.initials: SS
authors.lastname: Tungteakkhun
authors.forename: Kadia
authors.initials: K
authors.lastname: Williams
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Duerksen-Hughes
mesh_terms: D053181:Caspase 8 / Q000378:metabolism*; D004795:Enzyme Stability; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D052140:Human papillomavirus 11 / Q000276:immunology / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000276:immunology / Q000378:metabolism*; D052163:Human papillomavirus 6 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D053200:Fas-Associated Death Domain Protein; D009856:Oncogene Proteins, Viral; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D053181:Caspase 8