The papillomavirus E2 proteins.

HPVs (human papillomaviruses) infect epithelial cells and their replication cycle is intimately linked to epithelial differentiation. There are over 200 different HPV genotypes identified to date and each displays a strict tissue specificity for infection. HPV infection can result in a range of benign lesions, for example verrucas on the feet, common warts on the hands, or genital warts. HPV infects dividing basal epithelial cells where its dsDNA episomal genome enters the nuclei. Upon basal cell division, an infected daughter cell begins the process of keratinocyte differentiation that triggers a tightly orchestrated pattern of viral gene expression to accomplish a productive infection. A subset of mucosal-infective HPVs, the so-called ‘high risk’ (HR) HPVs, cause cervical disease, categorized as low or high grade. Most individuals will experience transient HR-HPV infection during their lifetime but these infections will not progress to clinically significant cervical disease or cancer because the immune system eventually recognizes and clears the virus. Cancer progression is due to persistent infection with an HR-HPV. HR-HPV infection is the cause of >99.7% cervical cancers in women, and a subset of oropharyngeal cancers, predominantly in men. HPV16 (HR-HPV genotype 16) is the most prevalent worldwide and the major cause of HPV-associated cancers. At the molecular level, cancer progression is due to increased expression of the viral oncoproteins E6 and E7, which activate the cell cycle, inhibit apoptosis, and allow accumulation of DNA damage. This review aims to describe the productive life cycle of HPV and discuss the roles of the viral proteins in HPV replication. Routes to viral persistence and cancer progression are also discussed.

The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review

Structural disorder in viral proteins.

Bin Xue,† David Blocquel, Johnny Habchi, Alexey V. Uversky, Lukasz Kurgan, Vladimir N. Uversky,*,‡,∇ and Sonia Longhi* †Department of Cell Biology, Microbiology and Molecular Biology, College of Fine Arts and Sciences, and ‡Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33620, United States Architecture et Fonction des Macromolecules Biologiques (AFMB) UMR 7257, Aix-Marseille Universite, 13288 Marseille, France AFMB UMR 7257, CNRS, 13288 Marseille, France Center for Data Analytics and Biomedical Informatics, Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, United States Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada T6G 2R3 Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Russia

Structural disorder in viral proteins

The papillomavirus (PV) E2 proteins have been shown to exert many functions in the viral cycle including pivotal roles in transcriptional regulation and in viral DNA replication. Besides these historical roles, which rely on their aptitude to bind to specific DNA sequences, E2 has also been shown to modulate the host cells through direct protein interactions mainly through its amino terminal transactivation domain. We will describe here some of these new functions of E2 and their potential implication in the HPV-induced carcinogenesis. More particularly we will focus on E2-mediated modulation of the host cell cycle and consequences to cell transformation. In all, the HPV E2 proteins exhibit complex functions independent of transcription that can modulate the host cells in concert with the viral vegetative cycle and which could be involved in early carcinogenesis.

Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression.

E7 is the major transforming activity in human papillomaviruses, a causal agent for cervical cancer. HPV16 E7 is a small protein with a natively unfolded domain for which dozens of specific cellular targets were described, and represents a prototypical oncoprotein among small DNA tumor viruses. The protein can form spherical oligomers with amyloid-like properties and chaperone activity. Conformation specific antibodies locate endogenous oligomeric E7 species in the cytosol of 3 model cell lines, strongly co-localizing with amyloid structures and dimeric E7 localizes to the nucleus. The cytosolic oligomeric E7 appear as the most abundant species in all cell systems tested. We show that nuclear E7 levels are replenished dynamically from the cytosolic pool and do not result from protein synthesis. Our results suggest that long-term events related to de-repression of E7 would cause accumulation of excess E7 into oligomeric species in the cytosol. These, together with the known target promiscuity of E7, may allow interactions with many of the non-pRb dependent targets described. This hypothesis is further supported by the detection of E7 oligomers in the cytosol of cancerous cells from tissue biopsies.

Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: The amyloid–cancer connection

Fil: Smal, Clara. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires. Fundacion Instituto Leloir. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Instituto de Quimica Biologica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Quimica Biologica de la Facultad de Ciencias Exactas y Naturales; Argentina

Karina I. Dantur

Papers

Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: The amyloid–cancer connection

The human papillomavirus E7-E2 interaction mechanism in vitro reveals a finely tuned system for modulating available E7 and E2 proteins.