Author(s): Marietta Müller aff1 , Emma L Prescott aff1 , Christopher W Wasson aff1 , Andrew Macdonald [*] aff1
cancer; E5; growth factor receptor; HPV; oncogene; signaling
Human papillomaviruses (HPV) are small dsDNA viruses that infect both mucosal and cutaneous epithelia and cause a range of lesions from benign warts and verrucas to cancer of the anogenital and oropharyngeal tracts. A small subgroup of HPV are considered high-risk due to their association with cancer. The 8-kb HPV genome codes for six early (E1, E2, E4, E5, E6 and E7) and two late (L1 and L2) proteins. The major oncoproteins encoded by HPV are E6 and E7, which have been extensively studied, however, there is also a minor oncoprotein termed E5, whose functions remain to be fully elucidated. This review article will summarize our current understanding of the roles of E5 in virus replication, describe the recognized interactions with host signaling pathways and discuss the validity of E5 as a potential target for direct-acting antiviral therapeutics.
General characteristics of HPV E5
While E6 and E7 are thought to provide the primary transforming activities of high-risk HPV, E5 expression can augment their function and has been shown to contribute to tumor progression in vivo [1 ]. HPV E5 proteins are small, membrane bound and highly hydrophobic proteins, between 40 and 93 amino acids long, expressed by a subset of papillomaviruses [2 ]. The subcellular localization of HPV E5 is not clear, given that there is currently no E5-specific antibody reagent available. However, overexpression studies using epitope-tagged E5 have shown colocalization with markers associated with the endoplasmic reticulum, Golgi apparatus, perinuclear regions and plasma membrane [3 ]. E5 proteins encoded by high-risk HPV16 and HPV18 are 9.4 and 8.3 kDa, respectively, and contain three putative hydrophobic regions with [alpha] helical structure, which are proposed to function as transmembrane domains [ 4 ]. HPV16 E5 has been shown to oligomerize both in vitro and in cells, with oligomer formation driven not by the presence of disulphide linkages between cysteine residues, rather by hydrophobic interactions between individual E5 monomers [5,6 ]. E5 oligomerization results in the formation of a channel structure shown to permit the flow of fluorescent dyes from the lumen of artificial liposome membranes in vitro [5 ]. The channel forming abilities of E5 imply that it belongs to a growing family of channel-forming viral membrane proteins, termed viroporins, which have been shown to be important for a number of viruses including Influenza A virus (M2), HIV-1 (Vpu) and Hepatitis C virus (p7) [7 ]. These channels play a critical role in virus entry and egress and are thought to mediate these processes by modulating cellular ion homeostasis.
Despite its initial identification as a bona fide protein product in 1988 there is a remarkable lack of information concerning the nature of this often ignored protein. This is in part due to the extreme hydrophobic nature of E5, which precludes high levels of expression of recombinant E5 expression in bacteria or mammalian cells [5 ]. To...