Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation.
The biochemical mechanisms that underlie hypoxia-induced NF-kappaB activity have remained largely undefined. Here, we find that prolonged hypoxia-induced NF-kappaB activation is restricted to cancer cell lines infected with high-risk human papillomavirus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-kappaB activation in these systems. The molecular target of E6 in the NF-kappaB pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-kappaB pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-kappaB in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies.
An
Jiabin
J
Department of Medicine, VA Greater Los Angeles Healthcare System-West Los Angeles, Los Angeles, CA 90095, USA.
Mo
Deqiong
D
Liu
Huiren
H
Veena
Mysore S
MS
Srivatsan
Eri S
ES
Massoumi
Ramin
R
Rettig
Matthew B
MB
D000818:Animals; D002448:Cell Adhesion; D015687:Cell Hypoxia; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D024202:Electrophoretic Mobility Shift Assay; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000821:virology; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
C068651:E6 protein, Human papillomavirus type 16; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D008156:Luciferases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D010100:Oxygen