Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

Abstract

Viruses have developed sophisticated strategies to evade host defenses and facilitate the production and spread of progeny. In this study, we show that transfection of the human papillomavirus (HPV) 16 E6 oncogene into HCT116 cells provides protection from tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Additionally, we demonstrate that the protection provided by E6 is dose-dependent because higher levels of E6 provide greater protection. The mechanism underlying this protection involves a rapid reduction in the protein levels of both Fasassociated death domain (FADD) and procaspase 8, which results in suppression of the activation of caspases 8, 3 and 2. Interestingly, E6 does not interfere with the mitochondrial apoptotic pathway even though HCT116 cells have been classified as type II cells with regard to TRAIL signaling. These findings demonstrate that E6 has a more generalized effect on signaling by death ligands than was previously thought and support the notion that E6 can utilize p53-independent mechanisms to modulate cell survival.

TNFα-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation

“…We identified that TNFa/ CHX-induced LMP is not an apoptosis initiating, but amplifying process downstream of MOMP, and it is triggered by mitochondrial ROS generated as the result of a caspase-3-mediated cleavage of the p75 NDUFS1 subunit of complex I. A similar finding was obtained in two different cellular systems, MEFs and HeLa cells, although molecular tools for manipulating p75 levels were not available for MEFs, and HeLa cells were less sensitive to TNFa/CHX-induced apoptosis due to the expression of HPV E6 and E7 genes (Garnett et al, 2006;Filippova et al, 2002). The mitochondrial production of ROS by TNFa has been shown in previous reports, and it was also suggested that these ROS somehow contribute to the apoptotic or necrotic process (Kim et al, 2010;Lin et al, 2004;Shoji et la., 1995;Schulze et la., 1993;Shen and Pervaiz, 2006).…”

Human Papillomavirus and Related Diseases - From Bench to Bedside - A Clinical Perspective

“…In addition to the TNF pathway, E6 is capable of inhibiting apoptosis stimulated by both Fas and TRAIL pathways. This inhibition is mediated by E6 binding to and degradation of both the FADD adapter protein and the effector caspase-8 (Garnett et al, 2006). As the binding of FADD is not dependent on the conserved PDZ domain of high-risk E6, but rather by a new domain (Tungteakkhun et al, 2008), it is possible that other E6 proteins may inhibit these extrinsic pathways.…”

“…Moreover, HPV infected cells avoid this process of cell death by E6-mediated inactivation of p53. This oncogene interferes with other pro-apoptotic proteins of both extrinsic and intrinsic apoptotic pathways, such as Bak, FADD and pro-caspase 8 (Garnett et al, 2006;Narisawa-saito & Kiyono, 2007;Thomas & Bank, 1999). Thus, these two oncoproteins are essential factors for HPV-induced cellular immortalization, transformation and carcinogenesis.…”

Human Papillomaviruses Oncoproteins

“…E6 is involved in the blockage of apoptosis acting in both major apoptotic pathways: a. the extrinsic pathway, which triggers extracellular signals that induce the activation of "death receptors" on the cell surface: 1) E6 binds to the death receptor TNFR-1, inhibiting TNFR-1 association with the TRADD (TNFR1-associated death domain adapter molecule) and blocking TNFR-1 death domain mediated apoptosis [47]; 2) E6 inhibits apoptosis by binding and degrading both the FADD adapter protein and caspase-8 [53].…”

“…Although HPVs 26,53, and 66 are probably high-risk types limited data link them to cervix cancer [3]. HPV16 accounts for near 60% of the cervical cancer cases in most countries, followed by HPV-18, -31 and -45.…”