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.High-risk types of human papillomaviruses (HPV) are causative agents in most cases of cervical carcinoma and are frequently implicated in head and neck cancers, as well. Much of the transforming ability of this virus can be attributed to the activities of its E6 and E7 oncoproteins. The HPV type 16 (HPV-16) E6 oncogene is an early gene expressed during HPV infection that plays an important role in cellular immortalization and transformation. The best-known activity of E6 is its ability to accelerate the degradation of p53 (50); however, not all of its transforming ability can be attributed to this activity (42,46,54,67), and E6 is known to influence additional cellular functions, such as the regulation of transcription and DNA replication (18,23,28,29,30,36,43,49,68,70), epithelial organization and differentiation (6,9,11,64), cell-cell adhesion, polarity and proliferation control (20,27,32,33,41,62,63), the DNA damage response (26, 55), and apoptotic pathways (15,16,21,61,66,67).Activation of the extrinsic apoptotic pathway begins with the binding of a signaling molecule, such as tumor necrosis factor (TNF), FasL, or TRAIL (TNF-related apoptosis inducing ligand), to its receptor. The resulting conformational change in the receptor then allows it to bind to additional adaptor and effector molecules (such as TRADD in the case of TNF and FADD [Fas-associated death domain] for TNF, FasL, and TRAIL) and ultimately results in the binding to and activation of the initiator caspase procaspase 8 (reviewed in references 47, 70, and 71). Activated caspase 8 can then activate caspase 3, which initiates the dissolution of a number of cellular proteins and structures and ultimately leads to apoptosis. Our previous work has shown that the HPV-16 E6 oncoprotein interacts with the extrin...