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.

Equilibrium dissociation and unfolding of human papillomavirus E2 transactivation domain

“…1B). Dimerization studies on HPV16 E2 TAD demonstrated that substitution of R37 (equivalent to R41 of HPV18) abolished dimer formation [2]. The residue R41 is preserved while W42 is conserved in terms of its hydrophobicity across different papillomavirus types (Fig.…”

“…Based upon oncogenicity, they are divided into two subclasses, high-risk (HR) types including HPV16 or 18 that are associated with 70% cases of cervical cancer, and benign wart-causing low risk (LR) types such as HPV6 and 11. Tremendous divergence in pathogenesis of HPVs has evolved due to complex system of regulation mediated by protein-DNA and proteineprotein interactions between viral and host factors [2]. Particularly, the early protein E2 acts as a master regulator of the viral life-cycle.…”

“…TAD is a proteineprotein interaction domain that binds to the viral helicase E1 [7] and to various host proteins such as topoisomerase-I [2], Brd4 [8] and procaspase-8 [5]. Crystal structures of TAD reveal that it comprises two sub-domains, N1 and N2, packed antiparallel to one another and separated by two consecutive single helical turns [7,9,10].…”

Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes

“…1b). This allows for unregulated transcription of E6 and E7 genes, producing the corresponding E6 and E7 oncoproteins, respectively, through which the virus primarily exerts its oncogenic potential [28]. The E6 oncoprotein binds to E6AP ubiquitin-protein ligase, which causes constant polyubiquitination of the arguably most important tumor suppressor protein in humans, p53 [29] (Fig.…”

In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer

“…E2 protein functions are mediated through protein-protein interactions and through the binding of E2 to a palindromic DNA sequence ACCN 6 GGT, referred to as the E2 binding site (E2BS)15-17. E2BS merits consideration as a candidate sequence to drive the expression of therapeutic genes only in HPV-infected cells that express the HPV E2 protein.…”