Interleukin 1 receptor-associated kinase 4 (IRAK4) plays a dual role in Myddosome formation and Toll-like receptor signalling
Publication Year 2018-09, Volume 293, Issue #39, Page 15195-15207
Journal Title
Journal of Biological Chemistry
Publication Type
Journal Article
Toll-like receptors (TLRs) form part of the host innate immune system, in which they act as sensors of microbial and endogenous danger signals. Upon TLR activation, the intracellular Toll/Interleukin-1 receptor domains of TLR dimers intiate oligomerization of a multiprotein signalling platform comprising myeloid differentiation primary response 88 (MyD88) and members of the interleukin 1 receptor-associated kinase (IRAK) family. Formation of this Myddosome complex initiates signal transduction pathways leading to the activation of transcription factors and the production of inflammatory cytokines. To date, little is known about the assembly and disassembly of the Myddosome and about the mechanisms by which these complexes mediate multiple downstream signaling pathways. Here, we isolated Myddosome complexes from whole-cell lysates of TLR-activated primary mouse macrophages and from IRAK reporter macrophages to examine the kinetics of Myddosome assembly and disassembly. Using a selective inhibitor of IRAK4's kinase activity, we found that while TLR cytokine responses were ablated, Myddosome formation was stabilised in the absence of IRAK4's kinase activity. Of note, IRAK4 inhibition had only a minimal effect on NF-kappaB and mitogen-activate protein kinase (MAPK) signalling. In summary, our results indicate that IRAK4 has a critical scaffold function in Myddosome formation and that its kinase activity is dispensable for Myddosome assembly and activation of the NF-kappaB and MAPK pathways but is essential for MyD88-dependent production of inflammatory cytokines. Our findings suggest that the scaffold function of IRAK4 may be an attractive target for inhibiting inflammatory and autoimmune diseases.
WEHI Research Division(s)
PubMed ID
NHMRC Grants
NHMRC/1144282 NHMRC/1142354 NHMRC/1099262
Rights Notice
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Creation Date: 2018-08-15 03:28:49
Last Modified: 2018-10-22 11:28:04
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