Interleukin 1/Toll-like Receptor-induced Autophosphorylation Activates Interleukin 1 Receptor-associated Kinase 4 and Controls Cytokine Induction in a Cell Type-specific Manner

Cushing, Leah; Stochaj, Wayne R.; Siegel, Marshall M.; Czerwiński, Robert; Dower, Ken; Wright, Quentin G.; Hirschfield, Margaret; Casanova, Jean‐Laurent; Pïcard, Capucine; Puel, Anne; Lin, Lih-Ling; Rao, Vikram

doi:10.1074/jbc.m113.544809

Cited by 52 publications

(85 citation statements)

References 33 publications

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“…In this regard, IRAK‐4 kinase inhibitors have shown promise in preclinical testing . However, recent studies suggest the differential role of IRAK‐4 in regulating cytokine production in different cell types . Of particular interest, the inhibition of IRAK‐4 activation in human dermal fibroblasts was not effective in regulating IL‐1R– or TLR agonist–induced IL‐6 production, whereas its inhibition in human monocytes was effective in reducing IL‐6 levels .…”

Section: Discussionmentioning

confidence: 99%

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Singh

Umar

Riegsecker

et al. 2016

Arthritis & Rheumatology

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Background/Purpose Transforming growth factor β activated kinase 1 (TAK1) is a key MAPKKK family protein in interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), or toll-like receptor signaling. We examined the posttranslational modification of TAK1 and its therapeutic regulation in rheumatoid arthritis (RA). Methods The effect of TAK1, IRAK-1, or TRAF6 inhibition was evaluated in IL-1β-induced human RA synovial fibroblasts (RA-FLS). Western blotting, immunoprecipitation, and 20S proteasome assay were used to study the ubiquitination process in RA-FLS. The efficacy of epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory molecule, in regulating these processes in RA-FLS was evaluated. Molecular docking was performed to examine the interaction of EGCG with human TAK1, IRAK-1, and TRAF6. These findings were validated using a rat adjuvant-induced arthritis (AIA) model. Results Inhibition of TAK1, not IRAK-1 or TRAF6, completely abrogates IL-1β-induced IL-6 and IL-8 synthesis in RA-FLS. EGCG inhibits TAK1 phosphorylation at Thr184/187 and occupies the C174 position, an ATP-binding site, to inhibit its kinase activity. EGCG pretreatment also inhibits K63-autoubiquitination of TRAF6, a post-translational modification essential for TAK1 autophosphorylation, by forming stable hydrogen-bond at the K124 position on TRAF6. Furthermore, EGCG enhances associated deubiquitinase expression to rescue proteins from proteasomal degradation. Western blot analyses on the joint homogenates from rat AIA show a significant increase in K48-linked polyubiquitination, TAK1 phosphorylation, and TRAF6 expression when compared to the naïve group. Administration of EGCG (50 mg/kg/day) for 10 days ameliorates AIA by reducing TAK1 phosphorylation and K48 polyubiquitination. Conclusions This study provides rationale for targeting TAK1 for RA treatment by EGCG.

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Section: Discussionmentioning

confidence: 99%

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Singh

Umar

Riegsecker

et al. 2016

Arthritis & Rheumatology

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“…The interaction of the DD of MyD88 and IRAK‐1 can be destabilized by phosphorylation within the DD . The linker region between the DDs and the conserved kinase domain is subject to massive auto‐phosphorylation at different residues in IRAK‐4 and especially IRAK‐1, and most likely serves 2 different roles. First, introduction of several negative charges in the ProST region further destabilizes the interaction with MyD88 allowing the dissociation of IRAK‐1 oligomers out of the receptor complex, and secondly within this region 2 so‐called PEST regions have been identified, which facilitate rapid degradation of IRAK‐1 after polyubiquitination via the proteasome, regulating the protein half‐life of IRAK‐1 after activation of IL‐1R …”

Section: Membrane‐proximal Signaling Events In the Tir Domain‐containmentioning

confidence: 99%

“…MyD88 and IRAK‐4 thus create a platform for the recruitment of further proteins such as IRAK‐1 and IRAK‐2, Tollip, and Pellino (reviewed in ). It was assumed that IRAK‐4 then trans‐auto‐phosphorylates, resulting in an enzymatically active protein kinase. Very recent results, however, question whether in fact IRAK‐4 must be enzymatically active to kick off downstream signaling via IRAK‐1 .…”

Section: Membrane‐proximal Signaling Events In the Tir Domain‐containmentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

275

225

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The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

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“…Recent discoveries such as the cell specific regulation of IL-6 production by TLR dependent autophosphorylation of IRAK-4 [28] may turn out to be pivotal in our understanding of IRAK-M as an inhibitor of IRAK-4 dependent processes. It should be stressed that while we used a theoretical 3D model to rationalize the in vitro experiments, our results show the involvement of the different residues of IRAK-M at the functional level only.…”

Section: Discussionmentioning

confidence: 99%

The structure function of the death domain of human IRAK-M

Nicolaes

Kruijswijk

et al. 2014

Cell Communication and Signaling

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Background: IRAK-M is an inhibitor of Toll-like receptor signaling that acts by re-directing IRAK-4 activity to TAK1 independent NF-κB activation and by inhibition of IRAK-1/IRAK-2 activity. IRAK-M is expressed in monocytes/macrophages and lung epithelial cells. Lack of IRAK-M in mice greatly improves the resistance to nosocomial pneumonia and lung tumors, which entices IRAK-M as a potential therapeutic target. IRAK-M consists of an N-terminal death domain (DD), a dysfunctional kinase domain and unstructured C-terminal domain. Little is known however on IRAK-M's structure-function relationships.

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Interleukin 1/Toll-like Receptor-induced Autophosphorylation Activates Interleukin 1 Receptor-associated Kinase 4 and Controls Cytokine Induction in a Cell Type-specific Manner

Cited by 52 publications

References 33 publications

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

The family of the interleukin‐1 receptors

The structure function of the death domain of human IRAK-M

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Interleukin 1/Toll-like Receptor-induced Autophosphorylation Activates Interleukin 1 Receptor-associated Kinase 4 and Controls Cytokine Induction in a Cell Type-specific Manner

Cited by 52 publications

References 33 publications

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K63‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K63‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

The family of the interleukin‐1 receptors

The structure function of the death domain of human IRAK-M

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Product

Resources

About

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6

Regulation of Transforming Growth Factor β–Activated Kinase Activation by Epigallocatechin‐3‐Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K⁶³‐Linked Autoubiquitination of Tumor Necrosis Factor Receptor–Associated Factor 6