title: High-risk HPV16E6 stimulates hADA3 degradation by enhancing its SUMOylation.
abstract: Despite significant research, our understanding of the molecular mechanisms of Human Papilloma Virus (HPV) induced cancers remains incomplete. Majority of invasive cervical cancers are caused by high-risk HPV 16 and 18. Two potent HPV oncoproteins, E6 and E7, promote human malignancies by disrupting the activities of key regulators of cell proliferation and apoptosis. Recent investigations have identified hADA3, a transcriptional coactivator protein as a target of high-risk HPV16E6. However, the mechanism of degradation of hADA3 by E6 and its contribution in HPV induced carcinogenesis is poorly understood. Here, we showed that E6-mediated proteolysis of hADA3 is responsible for maintaining low levels of hADA3 in HPV-positive cervical cancer cell lines. We demonstrate that HPV16E6 targets hADA3 for ubiquitin-mediated degradation via E6AP ubiquitin ligase. We also show that hADA3 undergoes accelerated SUMOylation in the presence of HPV16E6. Our data represent the first evidence that hADA3 is posttranslationally modified by SUMOylation, which makes it unstable and establishes a link between SUMOylation and E6-mediated ubiquitination of hADA3. Furthermore, depletion of Ubc9 prevented rapid degradation of hADA3 in E6 expressing cervical cancer cells and overexpression of hADA3 resulted in suppression of proliferation and migration abilities of SiHa cells. Overall, this study underscores the importance of posttranslational modifications in HPV16E6-mediated downregulation of hADA3 thereby unveiling a novel mechanism by which HPV induces oncogenesis.
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Chand
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
authors.forename: Rince
authors.initials: R
authors.lastname: John
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Jaiswal
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
authors.forename: Sumreet S
authors.initials: SS
authors.lastname: Johar
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India alonag22@gmail.com.
authors.forename: Alo
authors.initials: A
authors.lastname: Nag
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism*; D012307:Risk Factors; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054875:Ubiquitination; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014945:Wound Healing
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C444103:TADA3 protein, human; D014157:Transcription Factors