Complexes of human papillomavirus type 16 E6 proteins form pseudo-death-inducing signaling complex structures during tumor necrosis factor-mediated apoptosis.
High-risk strains of human papillomavirus (HPV) such as HPV type 16 (HPV16) and HPV18 are causative agents of most human cervical carcinomas. E6, one of the oncogenes encoded by HPV16, possesses a number of biological and transforming functions. We have previously shown that the binding of E6 to host apoptotic proteins such as tumor necrosis factor (TNF) R1, the adaptor protein FADD, and procaspase 8 results in a significant modification of the normal flow of apoptotic events. For example, E6 can bind to and accelerate the degradation of FADD. In addition, full-length E6 binds to the TNF R1 death domain and can also bind to and accelerate the degradation of procaspase 8. In contrast, the binding of small splice isoforms known as E6* results in the stabilization of procaspase 8. In this report, we propose a model for the ability of HPV16 E6 to both sensitize and protect cells from TNF as well as to protect cells from Fas. We demonstrate that both the level of E6 expression and the ratio between full-length E6 and E6* are important factors in the modification of the host extrinsic apoptotic pathways and show that at high levels of E6 expression, the further sensitization of U2OS, NOK, and Ca Ski cells to TNF-mediated apoptosis is most likely due to the formation of a pseudo-death-inducing signaling complex structure that includes complexes of E6 proteins.
Filippova
Maria
M
Department of Basic Sciences, Loma Linda University School of Medicine, 11085 Campus Street, 121 Mortensen Hall, Loma Linda, CA 92354, USA.
Filippov
Valery A
VA
Kagoda
Mercy
M
Garnett
Theodore
T
Fodor
Nadya
N
Duerksen-Hughes
Penelope J
PJ
D017209:Apoptosis; D002460:Cell Line; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D020033:Protein Isoforms; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor