Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria.
Apoptotic elimination of UV-damaged cells from the epidermis is an important step in preventing both the emergence and expansion of cells with carcinogenic potential. A pivotal event in apoptosis is the release of apoptogenic factors from the mitochondria, although the mechanisms by which the different proteins are released are not fully understood. Here we demonstrate that UV radiation induced the mitochondrial to nuclear translocation of apoptosis inducing factor (AIF) in normal skin. The human papillomavirus (HPV) E6 protein prevented release of AIF and other apoptotic factors such as cytochrome c and Omi from mitochondria of UV-damaged primary epidermal keratinocytes and preserved mitochondrial integrity. shRNA silencing of Bak, a target for E6-mediated proteolysis, demonstrated the requirement of Bak for UV-induced AIF release and mitochondrial fragmentation. Furthermore, screening non-melanoma skin cancer biopsies revealed an inverse correlation between HPV status and AIF nuclear translocation. Our results indicate that the E6 activity towards Bak is a key factor that promotes survival of HPV-infected cells that facilitates tumor development.
Leverrier
Sabrina
S
CR-UK, Skin Tumour Laboratory, Centre for Cutaneous Research, London, UK.
Bergamaschi
Daniele
D
Ghali
Lucy
L
Ola
Ayodele
A
Warnes
Gary
G
Akgül
Baki
B
Blight
Ken
K
García-Escudero
Ramón
R
Penna
Aubin
A
Eddaoudi
Ayad
A
Storey
Alan
A
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C494772:BAK1 protein, human; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D024101:Mitochondrial Proteins; D009856:Oncogene Proteins, Viral; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2