Mechanism of hypoxia-induced NF-kappaB.

Abstract:

: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.

journal_name

Mol Cell Biol

authors

Culver C,Sundqvist A,Mudie S,Melvin A,Xirodimas D,Rocha S

doi

10.1128/MCB.00409-10

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

4901-21

issue

20

eissn

0270-7306

issn

1098-5549

pii

MCB.00409-10

journal_volume

30

pub_type

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