UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

2018-09-28

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Hemic and Immune Systems | Immunity | Immunology of Infectious Disease

Abstract

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-kappaB 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-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 treating inflammatory and autoimmune diseases.

Keywords

IRAK1, IRAK4, NF-kappaB, Toll-like receptor (TLR), inflammation, innate immunity, interleukin-1 receptor-associated kinase, macrophage, myddosome, myeloid differentiation primary response gene (88) (MYD88), scaffold protein

Rights and Permissions

Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license. © 2018 De Nardo et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.

DOI of Published Version

10.1074/jbc.RA118.003314

Source

J Biol Chem. 2018 Sep 28;293(39):15195-15207. doi: 10.1074/jbc.RA118.003314. Epub 2018 Aug 3. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID

30076215

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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