Mechanism of Hypoxia-Induced NF-kappa B

Carolyn Culver, Anders Sundqvist, Sharon Mudie, Andrew Melvin, Dimitris Xirodimas, Sonia Rocha (Lead / Corresponding author)

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    130 Citations (Scopus)

    Abstract

    NF-kappa B 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, I kappa B kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)dependent pathway distinct from that for other common inducers of NF-kappa B. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NF-kappa B, 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-kappa B inducers, IKK-mediated phosphorylation of I kappa B alpha does not result in its degradation. We show that this results from I kappa B alpha 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 I kappa B alpha and activate NF-kappa B target genes. These results define a novel pathway regulating NF-kappa Bactivation, important to its physiological role in human health and disease.

    Original languageEnglish
    Pages (from-to)4901-4921
    Number of pages21
    JournalMolecular and Cellular Biology
    Volume30
    Issue number20
    DOIs
    Publication statusPublished - 10 Oct 2010

    Keywords

    • ALTITUDE PULMONARY-EDEMA
    • ARF TUMOR-SUPPRESSOR
    • ENDOTHELIAL-CELLS
    • TRANSCRIPTION FACTORS
    • KINASE TAK1
    • ACTIVATION
    • PATHWAY
    • OXYGEN
    • ROLES
    • TAB1

    Cite this

    Culver, C., Sundqvist, A., Mudie, S., Melvin, A., Xirodimas, D., & Rocha, S. (2010). Mechanism of Hypoxia-Induced NF-kappa B. Molecular and Cellular Biology, 30(20), 4901-4921. https://doi.org/10.1128/MCB.00409-10