Back to Search
Start Over
Interleukin-1 receptor–associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling
- Source :
- The journal of biological chemistry 293(39), 15195-15207 (2018). doi:10.1074/jbc.RA118.003314, The Journal of Biological Chemistry
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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-κB 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-κB 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.
- Subjects :
- 0301 basic medicine
Scaffold protein
genetics [Myeloid Differentiation Factor 88]
genetics [Mitogen-Activated Protein Kinase Kinases]
Biochemistry
genetics [Toll-Like Receptors]
Toll-like receptor (TLR)
Mice
0302 clinical medicine
interleukin-1 receptor-associated kinase
NF-kappaB
Phosphorylation
innate immunity
Toll-like receptor
myddosome
Chemistry
Toll-Like Receptors
NF-kappa B
IRAK1
myeloid differentiation primary response gene (88) (MYD88)
IRAK4
3. Good health
Cell biology
Interleukin-1 Receptor-Associated Kinases
030220 oncology & carcinogenesis
ddc:540
IRAK4 protein, human
Signal transduction
Signal Transduction
macrophage
chemistry [Macrophages]
Proinflammatory cytokine
chemistry [Toll-Like Receptors]
03 medical and health sciences
Animals
Humans
Irak4 protein, mouse
Kinase activity
Protein kinase A
Molecular Biology
Mitogen-Activated Protein Kinase Kinases
Macrophages
Cell Biology
chemistry [Myeloid Differentiation Factor 88]
030104 developmental biology
chemistry [Interleukin-1 Receptor-Associated Kinases]
inflammation
scaffold protein
Myeloid Differentiation Factor 88
metabolism [Macrophages]
genetics [Interleukin-1 Receptor-Associated Kinases]
genetics [NF-kappa B]
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....0f949fadbf9a2e683765ca66b89672f6