Mechanism of hypoxia-induced NF-kappaB.
NF-κB activation is a critical component in the transcriptional response to hypoxia. However, the underlying mechanisms that control its activity under these conditions are unknown. Here we report that under hypoxic conditions, IκB kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)-dependent pathway distinct from that for other common inducers of NF-κB. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NF-κB, but the TAK1-associated proteins TAB1 and TAB2 are not essential. IKK complex activation following hypoxia requires Ubc13 but not the recently identified LUBAC (linear ubiquitin chain assembly complex) ubiquitin conjugation system. In contrast to the action of other NF-κB inducers, IKK-mediated phosphorylation of IκBα does not result in its degradation. We show that this results from IκBα sumoylation by Sumo-2/3 on critical lysine residues, normally required for K-48-linked polyubiquitination. Furthermore, inhibition of specific Sumo proteases is sufficient to release RelA from IκBα and activate NF-κB target genes. These results define a novel pathway regulating NF-κB activation, important to its physiological role in human health and disease.
Culver
Carolyn
C
College of Life Sciences, Wellcome Trust Centre for Gene Regulation and Expression, MSI/WTB/JBC Complex, University of Dundee, Dundee, Scotland.
Sundqvist
Anders
A
Mudie
Sharon
S
Melvin
Andrew
A
Xirodimas
Dimitris
D
Rocha
Sonia
S
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D025842:SUMO-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D000099151:MAP Kinase Kinase Kinase 7
D004247:DNA; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D051996:Transcription Factor RelA; D000099151:MAP Kinase Kinase Kinase 7; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse