Insight into the Functional Interplay between the Full-length E6 Oncoprotein and E6*I Isoform of High-Risk Human Papillomaviruses Based upon Comparisons with Other Viral Synologues
Year: 2026
Type: other
Abstract: The high-risk alpha-genus human papillomaviruses (HPVs) infect basal stem cells within oropharyngeal and urogenital mucosal epithelia and can cause HPV+ uterine cervical cancers (CCs) and head-and-neck squamous cell carcinomas (HNSCCs). The reprogramming of infected differentiated epithelial cells and vegetative amplification of the HPV episomal dsDNA genome are mediated by the viral early proteins, E1, E2, E4, E5, E6, E7 and their alternative splice variants: E6*I, E6*II, and E6^E7. Intriguingly, E6*I is the most abundant E6-related transcript present in HPV-infected cells and its expression correlates with advancing degrees of cervical dysplasia and increases further in malignant CCs, and coincides with larger tumor sizes, therapy-resistance, and poor prognoses in HPV+ HNSCCs --yet relatively little is known about the role of E6*I in HPV pathogenesis. Using the PROMALS algorithm, we have identified conserved regions of structural and aa sequence similarities between the full-length E6 oncoprotein and E6*I isoform of high-risk HPVs and the human T-cell lymphotropic virus type-1 (HTLV-1) latency protein p30II and its splice variant, p13II, which suggests these unrelated transforming viruses may have evolved similar mechanisms to deregulate host pro-survival and proliferative signaling pathways. Our preliminary studies have demonstrated that HPV16/18 E6 cooperates with c-Myc, inhibits the MYST-family acetyltransferase TIP60 to prevent p53 K120-acetylation, and induces phosphorylation and mitochondrial targeting of the Tp53-induced glycolysis and apoptosis regulator (TIGAR) which suppresses oncogene-induced reactive oxygen species (ROS) to enhance the survival of HPV-infected cells. Like HTLV-1 p13II, the 18 E6*I isoform localizes to mitochondria and induces mt ROS, interacts with farnesyl pyrophosphate synthetase (FPPS) and induces the formation of tunneling nanotubules (TNTs) which support the intercellular trafficking of mitochondria. Moreover, TIGAR has been shown to interact with TGF-beta-activated kinase-1 (TAK1) and is required for recruitment of the E3 ligase, TRAF6, and TAK1-mediated phosphorylation of STING to activate NF kappa B- and IRF3-dependent innate immune responses. Based upon these findings, we hypothesize that E6 and E6*I functionally cooperate to deregulate host signaling pathways to promote the survival and proliferation of HPV-infected cells and could interfere with TIGAR-TAK1-STING-mediated antiviral immunosurveillance for the establishment of persistent high-risk HPV infections. The following specific aims are proposed: 1) To determine if the E6/E6*I-induced phosphorylation and mitochondrial targeting of TIGAR promotes mitochondrial quality control (MQC) to enhance the survival of HPV-infected cells. 2) To determine if the modulation of TIGAR by HPV E6/E6*I interferes with TIGAR-TAK1 molecular interactions and inhibits innate antiviral immune signaling. 3) To determine if E6*I-induced TNTs and the intercellular trafficking/infusion of mitochondria, containing E6*I, phospho-TIGAR, and FPPS, promote the reprogramming of stromal mesenchymal cells and the stealth transmission of HPV particles, and inhibit inflammatory signaling to establish persistent high-risk HPV infections.
Source: California Digital Library
DOI: 10.48321/d1ad6aa4f3
Author: Harrod, Robert
Institution: Southern Methodist University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7159640337