Novel cross-talk within the IKK family controls innate immunity

Kristopher Clark , Mark Peggie , Lorna Plater , Ronald J Sorcek , Erick Rr Young , Jeffrey B Madwed , Joanne Hough , Edward G Mciver , Philip Cohen (1)

1 MRC Protein Phosphorylation Unit

Members of the IκB kinase (IKK) family play a central role in innate immunity by inducing NFκB- and IRF-dependent gene transcription programmes required for the production of pro-inflammatory cytokines and interferons. However, the molecular mechanisms that activate these protein kinases and their complement of physiological substrates remain poorly defined. Using MRT67307, a novel inhibitor of IKKε/TBK1 and BI605906, a novel inhibitor of IKKβ, we demonstrate that two different signalling pathways participate in the activation of the IKK-related protein kinases by ligands that activate the IL-1, TLR3 and TLR4 receptors. One signalling pathway is mediated by the canonical IKKs, which directly phosphorylate and activate IKKε and TBK1, whereas the second pathway appears to culminate in the autocatalytic activation of the IKK-related kinases. In contrast, the TNFα-induced activation of the IKK-related kinases is mediated solely by the canonical IKKs. In turn, the IKK-related kinases phosphorylate the catalytic subunits of the canonical IKKs and their regulatory subunit NEMO, which is associated with reduced IKKα/β activity and NFκB-dependent gene transcription. We also show that the canonical IKKs and the IKK-related kinases not only have unique physiological substrates, such as IκBα, p105 and RelA (IKKα and IKKβ) and IRF3 (IKKε and TBK1), but also have several substrates in common, including the catalytic and regulatory (NEMO and TANK) subunits of the IKKs themselves. Taken together, our studies reveal that the canonical IKKs and the IKK-related kinases regulate each other by an intricate network involving phosphorylation of their catalytic and regulatory (NEMO, TANK) subunits to balance their activities during innate immunity.

Mots clés: Life Sciences

Kristopher Clark, Mark Peggie, Lorna Plater, Ronald J Sorcek, Erick Rr Young, et al.. Novel cross-talk within the IKK family controls innate immunity. Biochemical Journal, 2011, 434 (1), pp.93-104. ⟨10.1042/BJ20101701⟩. ⟨hal-00560693⟩