title: The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation.
abstract: High-risk human papillomavirus (HPV) must evade innate immune surveillance to establish persistent infections and to amplify viral genomes upon differentiation. Members of the JAK-STAT family are important regulators of the innate immune response and HPV proteins downregulate expression of STAT-1 to allow for stable maintenance of viral episomes. STAT-5 is another member of this pathway that modulates the inflammatory response and plays an important role in controlling cell cycle progression in response to cytokines and growth factors. Our studies show that HPV E7 activates STAT-5 phosphorylation without altering total protein levels. Inhibition of STAT-5 phosphorylation by the drug pimozide abolishes viral genome amplification and late gene expression in differentiating keratinocytes. In contrast, treatment of undifferentiated cells that stably maintain episomes has no effect on viral replication. Knockdown studies show that the STAT-5β isoform is mainly responsible for this activity and that this is mediated through the ATM DNA damage response. A downstream target of STAT-5, the peroxisome proliferator-activated receptor γ (PPARγ) contributes to the effects on members of the ATM pathway. Overall, these findings identify an important new regulatory mechanism by which the innate immune regulator, STAT-5, promotes HPV viral replication through activation of the ATM DNA damage response.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Hong
authors.forename: Laimonis A
authors.initials: LA
authors.lastname: Laimins
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics* / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010868:Pimozide / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C502189:E7 protein, Human papillomavirus type 31; D047495:PPAR gamma; D050725:Papillomavirus E7 Proteins; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D010868:Pimozide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins