The HPV E2-Host Protein-Protein Interactions: A Complex Hijacking of the Cellular Network

Abstract

Over 100 genotypes of human papillomaviruses (HPVs) have been identified as being responsible for unapparent infections or for lesions ranging from benign skin or genital warts to cancer. The pathogenesis of HPV results from complex relationships between viral and host factors, driven in particular by the interplay between the host proteome and the early viral proteins. The E2 protein regulates the transcription, the replication as well as the mitotic segregation of the viral genome through the recruitment of host cell factors to the HPV regulatory region. It is thereby a pivotal factor for the productive viral life cycle and for viral persistence, a major risk factor for cancer development. In addition, the E2 proteins have been shown to engage numerous interactions through which they play important roles in modulating the host cell. Such E2 activities are probably contributing to create cell conditions appropriate for the successive stages of the viral life cycle, and some of these activities have been demonstrated only for the oncogenic high-risk HPV. The recent mapping of E2-host protein-protein interactions with 12 genotypes representative of HPV diversity has shed some light on the large complexity of the host cell hijacking and on its diversity according to viral genotypes. This article reviews the functions of E2 as they emerge from the E2/host proteome interplay, taking into account the large-scale comparative interactomic study.

Keywords: E2; HPV; cervical cancer.; network; productive life cycle; protein interactions; viral pathogenesis.

Fig. (1)

HPV Long Control Region. (A) Schematic map of the long control region of HPV16. The end of the L1 and beginning of the E6 ORF are indicated. The E2 binding sites (E2BS) are numbered from 1 to 4 and colored in red. (B) Schematic representation of a prototypic genital HPV LCR with the position of the E2 and E1 binding sites. (C) Schematic representation of a prototypic cutaneous HPV LCR with the position of the E2 and E1 binding sites.

Fig. (2)

E2 proteins structure and interactions. HPV16 E2 threedimensional structure representing the three domains: Transactivation domain in the N-terminal part (TAD); Hinge unstructured domain in the centre, and DNA binding domain in the C-terminal part (DBD). A schematic representation of E2 is depicted below the 3D structure, with E2-interacting cellular proteins assigned to the interaction domain when it was determined.

Fig. (3)

Functional gathering of E2 interacting partners. DAVID analysis was performed on the E2 known interacting partners based on their associated GO (Gene Ontology) terms. Several parameters were taken into account to extract the four main categories: high enrichment score (A), low p-value (B), and high prevalence (C). (D) Representation of the four main functional families targeted by E2. Cellular proteins shared by different categories are multi-colored. The network representation was generated by Cytoscape [122].

Fig. (4)

Complex regulation of transcriptional mechanisms. (A) Known E2 interacting partners of the transcription family and their associated function either as transcription regulators or chromatin factors. (B) Summary of the interaction strength detected between 12 E2 proteins and cellular proteins involved in regulation of transcription. The symbol “-” stands for a lack of interaction and from “+” to “+++”, an increasing strength of interaction as measured in [15] (C) Gathering of E2 targets involved in transcription regulation by main function. (D) Representation of E2 association with the SNF2H-related chromatin remodeling complexes.

Fig. (5)

Cullin-based E3 ubiquitin ligase complexes. Schematic representation of three E3 ubiquitin ligase complexes that have been shown to be regulated by the HPV E2 proteins.

Fig. (6)

Intracellular transport and virus entry. Overlap between E2 targets involved in intracellular transport and the pathways of virus entry. EE: early endosome; LE: late endosome; ER: endoplasmic reticulum.