Nucleo-cytoplasmic shuttling of high risk human Papillomavirus E2 proteins induces apoptosis.
Human Papillomavirus (HPV) E2 proteins are the major viral regulators of transcription and replication during the viral life cycle. In addition to these conserved functions, we show that E2 proteins from high risk HPV types 16 and 18, which are associated with cervical cancer, can induce apoptosis. In contrast, E2 proteins from low risk HPV types 6 and 11, which are associated with benign lesions, do not cause cell death. We show that the ability to induce apoptosis is linked to the intracellular localization of the respective E2 proteins rather than to inherent properties of the proteins. Although low risk HPV E2 proteins remain strictly nuclear, high risk HPV E2 proteins are present in both the nucleus and the cytoplasm of expressing cells due to exportin-1 receptor (CRM1)-dependent nucleo-cytoplasmic shuttling. Induction of apoptosis is caused by accumulation of E2 in the cytoplasm and involves caspase 8 activation. We speculate that disruption of the E2 gene during viral genome integration in cervical carcinoma provides a means to avoid E2-induced apoptosis and allow initiation of carcinogenesis.
Blachon
Stéphanie
S
Unité Expression Génétique et Maladies, CNRS FRE 2850, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris cedex 15, France.
Bellanger
Sophie
S
Demeret
Caroline
C
Thierry
Françoise
F
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D016679:Genome, Viral; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism*; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000378:metabolism*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000821:virology*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D000097606:Exportin 1 Protein
D053181:Caspase 8; D020169:Caspases; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D028884:Karyopherins; D009856:Oncogene Proteins, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D014764:Viral Proteins; D000097606:Exportin 1 Protein; C117355:E2 protein, Human papillomavirus type 11; C054855:E2 protein, Human papillomavirus type 16; C505530:CASP8 protein, human