The human papillomavirus oncoproteins: a review of the host pathways targeted on the road to transformation

Abstract

Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis.

Keywords: HPV; cancer; keratinocyte; oncoprotein; signalling.

Fig. 1.

Dysregulation of the HPV life cycle can contribute to carcinogenesis. (a) HPV16 genome organization, displaying the position of viral transcripts. The URR, and early and late promoters are also highlighted. (b) Schematic representation of the development of cervical cancer. Cancer typically progresses from cervical intraepithelial neoplasia (CIN). CIN is classified using a three-stage system based on the proportion of the epithelium displaying abnormalities. CIN1 represents a transient HPV infection, whilst CIN2 and 3 represent a persistent HPV infection with a risk of progression to cancer. Epithelial layers are outlined on the left. CIS, carcinoma in situ. (c) HPV16 oncoprotein structure. Numbers refer to amino acid positions. TM, transmembrane domain; PBM, PDZ-binding motif; CR, conserved region; CKII, casein kinase II. Figure created using BioRENDER.com.

Fig. 2.

Summary of HPV E5 activities which contribute towards host-cell transformation. The host proteins and pathways reported to be modulated by HPV E5 are displayed, as well as the functional impact these have on the host cell. STAT, signal transducer and activator of transcription; MHC, major histocompatibility complex; EGFR, epidermal growth factor receptor; KGFR, keratinocyte growth factor receptor; AP-1, activator protein 1; FADD, Fas-associated protein with death domain. Figure created using BioRENDER.com.

Fig. 3.

Summary of HPV E6 activities which contribute towards host-cell transformation. The host proteins and pathways reported to be modulated by HPV E6 are displayed, as well as the functional impact these have on the host cell. hTERT, human telomerase reverse transcriptase; PI3K, phosphatidylinositol 3-kinase; NHERF1, Na⁺/H⁺ exchange regulatory factor 1; STAT, signal transducer and activator of transcription; JAK, Janus kinase; YAP1, Yes-associated protein 1; STK4, serine/threonine-protein kinase 4; CASP8, caspase-8; TNFR1, tumour necrosis factor receptor 1; BAK, Bcl-2 homologous antagonist/killer; FADD, Fas-associated protein with death domain; HMTs, histone methyltransferases; DNMT1, DNA methyltransferase 1; SNX27, sorting nexin 27; IRF3, IFN regulatory factor 3; TRIM25, tripartite motif-containing protein 25. Figure created using BioRENDER.com.

Fig. 4.

HPV E6 modulation of host signalling pathways. Summary of the mechanisms by which HR-HPV E6 dysregulates the host Hippo, PI3K/AKT, Wnt/β-catenin and JAK/STAT signalling pathways. See text for details. Figure created using BioRENDER.com.

Fig. 5.

Summary of HPV E7 activities which contribute towards host-cell transformation. The host proteins and pathways reported to be modulated by HPV E7 are displayed, as well as the functional impact these have on the host cell. PTPN14, protein tyrosine phosphatase non-receptor type 14; TGFβ, transforming growth factor beta; HDACs, histone deacetylases; SRC1, steroid receptor coactivator 1; DNMT1, DNA methyltransferase 1; KDM6A/B, lysine demethylase 6A/B; CDK2, cyclin-dependent kinase 2; pRb, retinoblastoma protein; DREAM, dimerization partner, pRb-like, E2F and multi-vulval class B; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3-related; IRF, IFN regulatory factor; TLR9, Toll-like receptor 9; cGAS, cyclic GMP-AMP synthase; STING, stimulator of IFN genes; IL-18BP, interleukin-18 binding protein. Figure created using BioRENDER.com.

Fig. 6.

Dysregulation of cell-cycle checkpoints by HPV E7. The mechanisms employed by HPV to include cell-cycle progression are illustrated. HPV E7 binds to and induces the degradation of the retinoblastoma protein (pRb) in a cullin 2 (CUL2) ubiquitin ligase-dependent manner. This releases the E2F1 transcription factor from inhibitory complexes, permitting the expression of genes associated with S-phase progression. Degradation of the related pocket proteins p107 and p130 prevents inhibition of G1 progression by the DREAM complex. HPV E7 also binds directly to cyclins A and E, potentiating cyclin-dependent kinase 2 (CDK2) activity. Further, HPV E7 can suppress the activity of the CDK inhibitors p21 and p27, allowing increased cyclin/CDK phosphorylation of pRb and enhanced E2F1-dependent transcription. HPV E6 also indirectly contributes towards cell-cycle progression: E6-associated protein (E6-AP)-dependent degradation of p53 prevents induction of p21 expression. Figure created using BioRENDER.com.