An Oligomeric Signaling Platform Formed by the Toll-like Receptor Signal Transducers MyD88 and IRAK-4

Motshwene, Precious G.; Moncrieffe, Martin C.; Grossmann, J. Günter; Kao, C. Cheng; Murali, Ayaluru; Sandercock, Alan M.; Robinson, Carol V.; Latz, Eicke

doi:10.1074/jbc.m109.022392

Cited by 336 publications

(319 citation statements)

References 41 publications

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“…Other TIR adapters, such as TIRAP for TLR2 and TLR4 (via MyD88), contribute to TLRresponsive pathways (21,22). IRAK-4 then associates with IRAK-1 and/or IRAK-2 to form the "Myddosome" (23)(24)(25)(26). The phosphorylation of IRAK-1 by IRAK-4 results in the activation of IRAK-1 kinase activity, leading to IRAK-1 hyperphosphorylation (by autophosphorylation).…”

mentioning

confidence: 99%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4-or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM 2 CSK 4 , LTA, FSL-1), TLR1/2 (PAM 3 CSK 4 ), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.IRAK-1 | IRAK-4 | Toll-like receptor | interleukin-1 receptor | primary immunodeficiency

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confidence: 99%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8,9). IRAK1 and IRAK2 can then interact with TRAF6 (10,11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity (13).…”

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confidence: 99%

Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling

Strickson

Emmerich

Goh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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It is widely accepted that the essential role of TRAF6 in vivo is to generate the Lys63-linked ubiquitin (K63-Ub) chains needed to activate the "master" protein kinase TAK1. Here, we report that TRAF6 E3 ligase activity contributes to but is not essential for the IL-1-dependent formation of K63-Ub chains, TAK1 activation, or IL-8 production in human cells, because Pellino1 and Pellino2 generate the K63-Ub chains required for signaling in cells expressing E3 ligaseinactive TRAF6 mutants. The IL-1-induced formation of K63-Ub chains and ubiquitylation of IRAK1, IRAK4, and MyD88 was abolished in TRAF6/Pellino1/Pellino2 triple-knockout (KO) cells, but not in TRAF6 KO or Pellino1/2 double-KO cells. The reexpression of E3 ligaseinactive TRAF6 mutants partially restored IL-1 signaling in TRAF6 KO cells, but not in TRAF6/Pellino1/Pellino2 triple-KO cells. Pellino1-generated K63-Ub chains activated the TAK1 complex in vitro with similar efficiently to TRAF6-generated K63-Ub chains. The early phase of TLR signaling and the TLR-dependent secretion of IL-10 (controlled by IRAKs 1 and 2) was only reduced modestly in primary macrophages from knockin mice expressing the E3 ligase-inactive TRAF6[L74H] mutant, but the late-phase production of IL-6, IL-12, and TNFα (controlled only by the pseudokinase IRAK2) was abolished. RANKLinduced signaling in macrophages and the differentiation of bone marrow to osteoclasts was similar in TRAF6[L74H] and wild-type cells, explaining why the bone structure and teeth of the TRAF6[L74H] mice was normal, unlike TRAF6 KO mice. We identify two essential roles of TRAF6 that are independent of its E3 ligase activity.T NF receptor-associated factor 6 (TRAF6) is essential for many biological processes (1). These include the myeloid differentiation primary response gene 88 (MyD88) signaling network of the innate immune system, RANK ligand (RANKL)-dependent signaling and osteoclast formation, lymph node organogenesis (2), and the development of hair follicles, sweat glands, and sebaceous glands (3). TRAF6 expression is also needed for CD40 signaling in B cells (4), the maturation and development of dendritic cells (5), and the regulation of T-cell function (6, 7).In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity (13).TRAF6 catalyzes the formation of Lys63-linked ubiquitin (K63-Ub) chains in vitro in the presence of Ubc13-Uev1a (also called UBE2N-UBE2V1), an E2 conjugating enzyme that directs the formation of this type of ubiquitin linkage (14, 15). Although truncated forms of TRAF6 lacking the really...

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“…Interactions between MyD88 and IRAK kinases are mediated in a DD-dependent manner. 8,9 To test whether Unc5CL can also interact with IRAKs, co-immunoprecipitation experiments have been performed (Figure 5e). Wild-type or kinase-dead IRAK4 (IRAK4 kd) were co-expressed with Unc5CL 432G, Unc5CLDDD or Unc5CL 432R.…”

Section: Resultsmentioning

confidence: 99%

“…MyD88 then nucleates the assembly of a ternary protein complex via DD-dependent recruitment and activation of the kinases IRAK1, IRAK2 and IRAK4. 8,9 Together with the E3-ubiquitin ligase TRAF6 these factors mediate further propagation of the signal. 10 The importance of the TLR/IL-1R signaling axis in health and disease is highlighted by the association with a multitude of human malignancies.…”

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confidence: 99%

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

et al. 2011

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An Oligomeric Signaling Platform Formed by the Toll-like Receptor Signal Transducers MyD88 and IRAK-4

Cited by 336 publications

References 41 publications

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

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