Abstract
BackgroundDuring 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 of pathogen associated molecules triggers the canonical NF-κB pathway that depends on the phosphorylation of Inhibitor of NF-κB (IκB) by the catalytic subunit IκB kinase β (IKKβ), its degradation and the nuclear translocation of NF-κB dimers.MethodologyHere, we performed an RNA interference (RNAi) screen on Shigella flexneri-induced NF-κB activation to identify new factors involved in the regulation of NF-κB following infection of epithelial cells by invasive bacteria. By targeting a subset of the human signaling proteome, we found that the catalytic subunit IKKα is also required for complete NF-κB activation during infection. Depletion of IKKα by RNAi strongly reduces the nuclear translocation of NF-κB p65 during S. flexneri infection as well as the expression of the proinflammatory chemokine interleukin-8. Similar to IKKβ, IKKα contributes to the phosphorylation of IκBα on serines 32 and 36, and to its degradation. Experiments performed with the synthetic Nod1 ligand L-Ala-D-γ-Glu-meso-diaminopimelic acid confirmed that IKKα is involved in NF-κB activation triggered downstream of Nod1-mediated peptidoglycan recognition.ConclusionsTaken together, these results demonstrate the unexpected role of IKKα in the canonical NF-κB pathway triggered by peptidoglycan recognition during bacterial infection. In addition, they suggest that IKKα may be an important drug target for the development of treatments that aim at limiting inflammation in bacterial infection.
Highlights
During pathogen infection, structurally conserved microbial molecules are recognized by germline-encoded pathogen recognition receptors (PRRs) that function as sensors for non-self detection and initiate innate immunity [1,2]
Taken together, these results demonstrate the unexpected role of IKKa in the canonical nuclear factor-kappa B (NF-kB) pathway triggered by peptidoglycan recognition during bacterial infection
They suggest that IKKa may be an important drug target for the development of treatments that aim at limiting inflammation in bacterial infection
Summary
Structurally conserved microbial molecules are recognized by germline-encoded pathogen recognition receptors (PRRs) that function as sensors for non-self detection and initiate innate immunity [1,2]. Signaling pathways of PAMP recognition converge into the activation of the pleiotropic transcription factor nuclear factor-kappa B (NF-kB) that, in the context of innate immunity, regulates the expression of proinflammatory genes encoding cytokines, chemokines, anti-bacterial peptides and adhesion molecules [7]. Most of the NF-kB dimers are sequestrated in the cytoplasm by the proteins of the Inhibitor of NF-kB (IkB) family whose prototype is IkBa. In the canonical pathway of NF-kB activation triggered by most stimuli including bacterial and viral infection, cytokines and stress-induced responses, phosphorylation of IkBa on Serine 32 and Serine 36 residues by the IkB kinase (IKK) complex is a decisive regulatory step [9]. In a typical model of NF-kB activation, the recognition of pathogen associated molecules triggers the canonical NF-kB pathway that depends on the phosphorylation of Inhibitor of NF-kB (IkB) by the catalytic subunit IkB kinase b (IKKb), its degradation and the nuclear translocation of NF-kB dimers
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