Dataset Information

IKK? contributes to canonical NF-?B activation downstream of Nod1-mediated peptidoglycan recognition.

ABSTRACT:

Background

During pathogen infection, innate immunity is initiated via the recognition of microbial products by pattern recognition receptors and the subsequent activation of transcription factors that upregulate proinflammatory genes. By controlling the expression of cytokines, chemokines, anti-bacterial peptides and adhesion molecules, the transcription factor nuclear factor-kappa B (NF-?B) has a central function in this process. In a typical model of NF-?B activation, the recognition of pathogen associated molecules triggers the canonical NF-?B pathway that depends on the phosphorylation of Inhibitor of NF-?B (I?B) by the catalytic subunit I?B kinase ? (IKK?), its degradation and the nuclear translocation of NF-?B dimers.

Methodology

Here, we performed an RNA interference (RNAi) screen on Shigella flexneri-induced NF-?B activation to identify new factors involved in the regulation of NF-?B following infection of epithelial cells by invasive bacteria. By targeting a subset of the human signaling proteome, we found that the catalytic subunit IKK? is also required for complete NF-?B activation during infection. Depletion of IKK? by RNAi strongly reduces the nuclear translocation of NF-?B p65 during S. flexneri infection as well as the expression of the proinflammatory chemokine interleukin-8. Similar to IKK?, IKK? contributes to the phosphorylation of I?B? on serines 32 and 36, and to its degradation. Experiments performed with the synthetic Nod1 ligand L-Ala-D-?-Glu-meso-diaminopimelic acid confirmed that IKK? is involved in NF-?B activation triggered downstream of Nod1-mediated peptidoglycan recognition.

Conclusions

Taken together, these results demonstrate the unexpected role of IKK? in the canonical NF-?B pathway triggered by peptidoglycan recognition during bacterial infection. In addition, they suggest that IKK? may be an important drug target for the development of treatments that aim at limiting inflammation in bacterial infection.

SUBMITTER: Kim ML

PROVIDER: S-EPMC2955547 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Publications

IKKα contributes to canonical NF-κB activation downstream of Nod1-mediated peptidoglycan recognition.

Kim Man Lyang ML Jeong Hyun Gyeong HG Kasper Christoph Alexander CA Arrieumerlou Cécile C

PloS one 20101015 10

<h4>Background</h4>During pathogen infection, innate immunity is initiated via the recognition of microbial products by pattern recognition receptors and the subsequent activation of transcription factors that upregulate proinflammatory genes. By controlling the expression of cytokines, chemokines, anti-bacterial peptides and adhesion molecules, the transcription factor nuclear factor-kappa B (NF-κB) has a central function in this process. In a typical model of NF-κB activation, the recognition ...[more]

PMID: 20976174

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