UV exposure is the main etiological agent in the development of non-melanoma skin cancer (NMSC), but mounting evidence suggests a co-factorial role for b-genus HPV types early in tumor initiation or progression. UV damage initiates an apoptotic response, driven at the mitochondrial level by BCL-2 family proteins, that eliminates damaged cells that may accumulate deleterious mutations and acquire tumorigenic properties. BAK is a pro-apoptotic BCL-2 protein that functions ultimately to form pores that permeabilize the mitochondrial outer membrane, thereby committing a cell to death, a process involving changes in BAK phosphorylation and conformation. The E6 protein of b-type HPV5 signals BAK for proteasomal degradation, a function that confers protection from UV-induced apoptosis. We find that HPV5 E6 does not constitutively target BAK for proteolysis, but targets the latter stages of BAK activation, following changes in phosphorylation and conformation. A mutational analysis identified the lysine residue on BAK required for proteolysis, and a functional siRNA screen identified the HECT domain E3 ubiquitin ligase HERC1 as being required for E6-mediated BAK degradation. We show that HERC1 interacts with BAK in E6-expressing cells that have been damaged by UV, and provide evidence that the interaction of HERC1 with BAK requires access to a hydrophobic surface on BAK that binds BH3 domains of BCL-2 proteins. We also show that HERC1 contains a putative BH3 domain that can bind to BAK. These findings reveal a specific and unique mechanism used by the HPV5 E6 protein to target BAK.
Beta-human papillomaviruses (b-HPV) infect cutaneous epithelia, and accumulating evidence suggests that the virus may act as a co-factor with UV-induced DNA damage in the development and progression of non-melanoma skin cancer, although the molecular mechanisms involved are poorly understood. The E6 protein of cutaneous b-HPV types encodes functions consistent with a role in tumorigenesis, and E6 expression can result in papilloma formation in transgenic animals. The E6 proteins of high-risk a-HPV types, which are associated with the development of anogenital cancers, have a conserved 4 aa motif at their extreme C terminus that binds to specific PDZ domain-containing proteins to promote cell invasion. Likewise, the high-risk b-HPVs HPV5 and HPV8 E6 proteins also share a conserved C-terminal motif, but this is markedly different from that of a-HPV types, implying functional differences. Using binding and functional studies, we have shown that b-HPV E6 proteins target b 1 -integrin using this C-terminal motif. E6 expression reduced membrane localization of b 1 -integrin, but increased overall levels of b 1 -integrin protein and its downstream effector focal adhesion kinase in human keratinocytes. Altered b 1 -integrin localization due to E6 expression was associated with actin cytoskeleton rearrangement and increased cell migration that was abolished by point mutations in the C-terminal motif of E6. We concluded that modulation of b 1 -integrin signalling by E6 proteins may contribute towards the pathogenicity of these b-HPV types. INTRODUCTIONUV-induced damage to keratinocytes is the main aetiological factor in the development of non-melanoma skin cancer (NMSC). Keratinocytes are the host cells of human papillomavirus (HPV) infection and the HPV life cycle is tightly coupled to the keratinocyte differentiation programme. HPVs encode genes that promote keratinocyte survival and proliferation after UV exposure and uncouple cell-cycle exit from differentiation (Hudson et al., 1990;Jones et al., 1997). Infection with high-risk b-HPVs is associated with the development of NMSC, the most commonly diagnosed cancer in Caucasians (Diepgen & Mahler, 2002;Kiviat, 1999). HPVs of the genus Betapapillomavirus (formerly known as Epidermodysplasia verruciformis or EV types) exhibit cutaneous tropism where EV individuals are prone to infection with these viral types. EV individuals have a propensity to develop NMSC at sunexposed body sites as early as the age of 20 years (Gül et al., 2007), where infection with the b1-HPV types 5 and 8 are associated with the highest risk of malignancy (Orth, 1986;Pfister, 2003;Pfister & Ter Schegget, 1997). In more recent epidemiological studies, a high percentage of squamous cell carcinoma (SCC) isolated from immunocompromised organ transplant recipients was found to contain b-HPV DNA (Harwood et al., , 2004Proby et al., 2011;Weissenborn et al., 2012) and the immunocompromised population has a 200-fold increased risk of SCC formation compared with the immunocompetent population (Hartevelt et a...
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