HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

Abstract

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer.

Keywords: E6; E7; HPV; UPS; cervical cancer; proteasome; ubiquitin; ubiquitin ligases.

Figure 1

The Ubiquitin Proteasome System (UPS) dependent activities of α- and β-HPV E6 oncoproteins. E6 oncoproteins from α and β types interact with various components of the UPS and as speculated use them to modulate a number of cellular processes. By interacting with the UPS components high-risk (HR) α-type HPV E6s are involved in the regulation of all the processes shown above; low-risk (LR) α-type E6s are involved in regulation of viral life cycle, modulation of E6AP activity, and regulation of the immune response; β-type HPV E6s are involved in regulation of the viral life cycle, modulation of E6AP activity, regulation of the immune response, and E6 oncoprotein stability.

Figure 2

The Ubiquitin Proteasome System (UPS) dependent activities of α- and β-HPV E7 oncoproteins. E7 oncoproteins from α and β types interact with various components of the UPS and are thought to use them to modulate a number of cellular processes. By interacting with the UPS components, high-risk (HR) α-type E7s are involved in the regulation of all the processes shown above; low-risk (LR) α-type E7s are involved in cell migration, apoptosis, regulation of the immune response, viral life cycle modulation and E7 protein turnover; β-type E7s are involved in cell migration, apoptosis, endosomal trafficking and regulation of the immune response.