| HPV18 E6, a multifunctional oncoprotein encoded by the high-risk human papillomavirus type 18, belongs to the E6 family of viral proteins that hijack host ubiquitin-proteasome machinery to drive cellular transformation in epithelial cells. It features a compact structure with two zinc-binding domains stabilized by conserved CXXHXXC motifs, enabling high-affinity interactions with cellular partners through its flexible hinge region. The core mechanism revolves around E6 forming a ternary complex with the cellular E3 ubiquitin ligase E6AP, which recruits and polyubiquitinates the tumor suppressor p53 for proteasomal degradation, thereby abolishing p53-mediated transcriptional activation of cell cycle inhibitors like p21 and DNA repair genes; this unleashes G1/S checkpoint override and genomic instability favoring viral persistence and oncogenesis. Beyond p53, E6/E6AP targets additional substrates including TP73, BAK1, and procaspase-8, crippling intrinsic and extrinsic apoptosis pathways while activating telomerase via NFX1 degradation to sustain replicative immortality. E6 further intersects the interferon signaling cascade by binding IRF3 to block its dimerization and phosphorylation, suppressing type I IFN production, and interacting with TYK2 to dampen JAK-STAT activation, which collectively evades innate antiviral immunity. Dysregulation amplifies in persistent infections progressing to CIN2/3 lesions and invasive carcinoma, with E6 variants influencing metastatic potential. |
Lane 1: Hela
