The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections

Abstract

SUMMARY Infections by human papillomaviruses (HPVs) are the most frequently occurring sexually transmitted diseases. The crucial role of genital oncogenic HPV in cervical carcinoma development is now well established. In contrast, the role of cutaneous HPV in skin cancer development remains a matter of debate. Cutaneous beta-HPV strains show an amazing ubiquity. The fact that a few oncogenic genotypes cause cancers in patients suffering from epidermodysplasia verruciformis is in sharp contrast to the unapparent course of infection in the general population. Our recent investigations revealed that a natural barrier exists in humans, which protects them against infection with these papillomaviruses. A central role in the function of this HPV-specific barrier is played by a complex of the zinc-transporting proteins EVER1, EVER2, and ZnT-1, which maintain cellular zinc homeostasis. Apparently, the deregulation of the cellular zinc balance emerges as an important step in the life cycles not only of cutaneous but also of genital HPVs, although the latter viruses have developed a mechanism by which they can break the barrier and impose a zinc imbalance. Herein, we present a previously unpublished list of the cellular partners of EVER proteins, which points to future directions concerning investigations of the mechanisms of action of the EVER/ZnT-1 complex. We also present a general overview of the pathogenesis of HPV infections, taking into account the latest discoveries regarding the role of cellular zinc homeostasis in the HPV life cycle. We propose a potential model for the mechanism of function of the anti-HPV barrier.

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

“…29 The relationship between b-HPV infection and skin cancer has been clearly defined in patients suffering from the rare inherited disease epidermodysplasia verruciformis, an autosomal recessive disease characterized by a predisposition to infection by specific types of b-HPV. [30][31][32] In these patients, HPV5 and 8 replicate very efficiently and reveal their full transforming potential, inducing multiple cutaneous neoplasia. 33,34 Emerging evidence also supports the role of b-HPV in skin cancer development in immunosuppressed individuals.…”

Heterodimerization, Altered Subcellular Localization, and Function of Multiple Zinc Transporters in Viable Cells Using Bimolecular Fluorescence Complementation

“…The most established heterodimer was ZnT5-ZnT6, which was shown to function in the activation of tissue-nonspecific alkaline phosphatase at this heterodimer form (21). In a previous review, Lazarczyk et al (32) described the ability of ZnT1 to interact with either EVER1/EVER2 proteins, ZnT1-4, or ZnT7, as revealed by a yeast two-hybrid screening assay. However, experimental data that pinpoint these putative interactions and their functionality at their intracellular localization in viable mammalian cells have not been provided.…”

“…Previous studies showing homo-or heterodimerization in the ZnT family were based on biochemical assays combined with immunofluorescence microscopy co-localization of individual ZnTs in the same subcellular compartment (11,20,21,32). The most established heterodimer was ZnT5-ZnT6, which was shown to function in the activation of tissue-nonspecific alkaline phosphatase at this heterodimer form (21).…”

Human Papillomavirus: Biology and Pathogenesis

“…In the more differentiated cells of this same layer of the epithelium occurs the activation of differentiation-dependent promoter and maintenance of gene expression E1, E2, E6 and E7. Furthermore, there will be activation of the expression of E4 gene, whose product will induce amplification of the viral genome replication, greatly increasing the number of virus copies per cell, at the same time that occurs the expression of genes L1 and L2 (Nakahara et al, 2005;Lazarczyk et al, 2009). In the granular layer, the products of late genes, the major and minor proteins of the viral capsid, L1 and L2 respectively, gather to assembly of the viral capsids and formations of virions, which reach cornified layer of the epithelium and are released (Lazarczyk et al, 2009).…”

“…These proteins bind to the viral origin of replication and recruit cellular DNA polymerases and other proteins necessary for DNA replication (Hamid et al, 2009). In the suprabasal layer, the expression of genes E1, E2, E5, E6 and E7 contributes to the maintenance of the viral genome and induces cell proliferation , increasing the number of HPV-infected cells in the epithelium, resulting in a higher number of cells that will eventually produce infectious virions (Hamid & Gston, 2009;Lazarczyk et al, 2009). In the more differentiated cells of this same layer of the epithelium occurs the activation of differentiation-dependent promoter and maintenance of gene expression E1, E2, E6 and E7.…”