IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase

Li, Shyun; Strelow, Astrid; Fontana, Elizabeth J.; Wesche, Holger

doi:10.1073/pnas.082100399

Cited by 613 publications

(478 citation statements)

References 28 publications

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“…Although the exact significance of this interaction is under investigation, we can hypothesize that PKC-a could target immediate MyD88 downstream mediators such as IRAK1, IRAK4 or TNF receptor-associated factor 6, which control both NF-kB and AP-1 activation in the MyD88-dependent pathway [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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Conventional PKC (cPKC)-a regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-a is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö 6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-a repressed Pam 3 CSK 4 induced NF-jB-and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-jB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-a À/À mice exhibited decreased TNF-a and IL-12p40 production induced by both MyD88-and TRIF-dependent ligands. Furthermore, PKC-a is coupled to TLR2 signaling proximal to MyD88 since MAPK and IjB kinase-a/b phosphorylations and IjBa degradation were inhibited in PKC-a À/À BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-a physically interacts with Pam 3 CSK 4 activated TLR2 in WT but not in MyD88 À/À DC. Collectively this study identifies a species-specific role of PKC-a as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.Key words: MyD88 . PKC . TLR Supporting Information available online Introduction TLR are a family of evolutionary conserved transmembrane proteins that are expressed on numerous cell types including Mf and DC. They function as pathogen recognition receptors, sensing a wide range of invading pathogens including bacteria, fungi and viruses through recognition of PAMP. Engagement of TLR by microbial products triggers the activation of two distinct signaling pathways: the MyD88-dependent and -independent pathways, Ã These authors contributed equally to this work.ÃÃ These authors contributed equally to this work. [4,5]. Recent studies identified several PKC isoforms as key regulators of TLR signaling pathways. PKC serine/threonine kinase family is classified into three groups according to their structure homology and co-factor regulation (conventional PKC (a, bI, bII, and g), novel PKC (d, e, y and Z/L) and atypical PKC (l/i and z)) [6,7]. PKC-e À/À Mf display a major defect in their ability to generate inflammatory mediators in response to LPS and are highly susceptible to Gram-positive and Gram-negative infections [8,9]. PKC-e is also involved in LPS-induced MAPK phosphatase 1 expression in MF and plays a critical role in LPS-induced IL-12p70 and TNF-a production in DC [10,11]. PKC-e À/À and PKC-d À/À MF display an impaired activation of NF-kB and MAPK downstream of TLR2 and TLR4 [8,12]. PKC-d is necessary to induce Stat-1 activation in response to LPS in murine MF [13]. PKC-z is implicated in LPS-induced MAPK and NF-kB...

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Section: Discussionmentioning

confidence: 99%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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“…MyD88 also contains a death domain that facilitates the subsequent recruitment of death-domain-containing IRAK1 and IRAK4 to the receptor complex [2] where IRAK1 is phosphorylated and activated by IRAK4 [5][6][7]. This is followed by intensive autophosphorylation of IRAK1 [5,6], its interaction with TRAF6 and subsequent dissociation of IRAK1 and TRAF6 as binding partners from the receptor complex [8][9][10]. TRAF6 then interacts with TIFA (TRAF-interacting protein with a FHA domain), which promotes oligomerization and ubiquitylation (Box 1) of the former [11].…”

Section: The Importance Of Pellino Proteins For Tlr Signallingmentioning

confidence: 99%

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Moynagh

2009

Trends in Immunology

132

102

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“…IRAK-1 is recruited to Myd88 within a complex with another protein termed Tollinteracting protein (Tollip) [3]. The IRAK-Myd88 association triggers hyperphosphorylation of IRAK-1 by itself and other kinases, such as IRAK-4 [4,5], which leads to its dissociation from Myd88 and Tollip and its interaction with the downstream adaptor tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF-6) [3]. TRAF-6 is an ubiquitin ligase [6,7] and activates transforming growth factor-b (TGF-b)-activating kinase (TAK1) [8], which in turn promotes downstream activation of the IkB kinases (IKK), IKKa and IKKb.…”

Section: Myd88-dependent Signalling and Activation Of Nf-kbmentioning

confidence: 99%

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

Moynagh

2005

Trends in Immunology

283

215

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IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase

Cited by 613 publications

References 28 publications

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

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