Comparative Analysis of Alpha and Beta HPV E6 Oncoproteins: Insights into Functional Distinctions and Divergent Mechanisms of Pathogenesis

Abstract

Human papillomaviruses (HPVs) represent a diverse group of DNA viruses that infect epithelial cells of mucosal and cutaneous tissues, leading to a wide spectrum of clinical outcomes. Among various HPVs, alpha (α) and beta (β) types have garnered significant attention due to their associations with human health. α-HPVs are primarily linked to infections of the mucosa, with high-risk subtypes, such as HPV16 and HPV18, being the major etiological agents of cervical and oropharyngeal cancers. In contrast, β-HPVs are predominantly associated with cutaneous infections and are commonly found on healthy skin. However, certain β-types, notably HPV5 and HPV8, have been implicated in the development of non-melanoma skin cancers in immunocompromised individuals, highlighting their potential role in pathogenicity. In this review, we comprehensively analyze the similarities and differences between α- and β-HPV E6 oncoproteins, one of the major drivers of viral replication and cellular transformation, and how these impact viral fitness and the capacity to induce malignancy. In particular, we compare the mechanisms these oncoproteins use to modulate common cellular processes-apoptosis, DNA damage repair, cell differentiation, and the immune response-further shedding light on their shared and distinct features, which enable them to replicate at divergent locations of the human body and cause different types of cancer.

Keywords: E6 oncoprotein; HNSCC; alpha-HPV; beta-HPV; cSCC; cervical cancer.

Figure 1

Differences in genome organization, viral life cycle, and malignant progression between α- and β-HPVs. (A) HR-HPVs infect mucosal epithelia via micro-wounds, and they manipulate differentiating cells to efficiently propagate new virions, with viral gene expression (light blue—oncoproteins, orange—other early proteins and capsid proteins) coinciding with the stages of keratinocyte maturation (middle panel). As basal cells become dysplastic, the viral gene expression becomes more disordered, while E6/E7 acquire the primacy in expression over other proteins. This process leads to a reduced productive infection, resulting in the release of fewer virions (right panel). Premalignant stages are also indicated (LSIL—low-grade squamous interepithelial lesion; HSIL—high-grade squamous interepithelial lesion). (B) The natural reservoir for HPV8 and many other β-types is considered to be cutaneous epithelia, including hair follicles. Their life cycle is also dependent on keratinocyte differentiation, with orchestrated expression of viral genes delaying keratinocyte maturation and enabling the production of new virions (middle panel). β-HPV genomes do not integrate into the host genome and are considered to act as cofactors in tumor initiation but are not necessary for tumor maintenance. The viral load is higher in premalignant states than in cSCC, and it is currently unknown whether β-HPVs can complete their life cycle in transformed cells (right panel). Expanded and adapted from [23].

Figure 2

The most important binding partners and target substrates of E6 oncoproteins. α-E6 exclusive interacting partners are indicated in the blue circle, β-E6 specific ones in the green circle, and common ones in the yellow overlap. * denotes that the protein is a partner of the β2 species, ⁺ refers that the protein is a partner of the β3 species, and ^$ refers that the protein is the partner of β4 species.

Figure 3

Strategies employed by E6 oncoproteins in manipulating p53 signaling. α- and β-E6 oncoproteins mostly have distinct ways of affecting p53. The ones typical for α-E6 are indicated in the blue box, and the ones typical for β-E6 in the green one. The mechanism shared between both E6 oncoproteins is indicated by the overlapping area. * denotes that the claim refers to β2 species, ⁺ that it refers to β3 and ^$ that it refers to β4.