Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 39, Pages 15195-15207Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003314
Keywords
innate immunity; Toll-like receptor (TLR); inflammation; myeloid differentiation primary response gene (88) (MYD88); macrophage; interleukin-1 receptor-associated kinase; IRAK4; IRAK1; myddosome; scaffold protein; NF-kappaB
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Funding
- BONFOR research commission (University of Bonn, Germany)
- National Institutes of Health [1R01AR066808-01A1]
- Excellence Cluster Immuno-Sensation
- German Research Foundation [TRR83, TRR57, SFB1123]
- NHMRC [1144282, 1142354, 1099262]
- Sylvia and Charles Viertel Foundation
- HHMI-Wellcome International Research Scholarship
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR066808] Funding Source: NIH RePORTER
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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 initiate oligomerization of a multiprotein signaling 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 whereas TLR cytokine responses were ablated, myddosome formation was stabilized in the absence of IRAK4's kinase activity. Of note, IRAK4 inhibition had only a minimal effect on NF-B and mitogen-activated protein kinase (MAPK) signaling. 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-B 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 treating inflammatory and autoimmune diseases.
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