Disease relevance of IRAK1

• These results suggest that variation of IRAK1 may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss [1].
• We analyzed 11 single nucleotide polymorphisms (four in IRAK1 and seven in IRAK4) among 1,383 newly diagnosed prostate cancer patients and 780 population controls in Sweden [2].
• CONCLUSION: The airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1 [3].
• Pharmacological targeting of particular IRAK components may be beneficial for treatment of bacterial infections [4].
• Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis [5].
• IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies [6].

High impact information on IRAK1

• When human embryonic kidney cells (cell line 293) over-expressing IL-1RI or HeLa cells were exposed to IL-1, IRAK rapidly associated with the IL-1RI complex and was phosphorylated [7].
• A protein kinase designated IRAK (IL-1 receptor-associated kinase) was purified, and its complementary DNA was molecularly cloned [7].
• The primary amino acid sequence of IRAK shares similarity with that of Pelle, a protein kinase that is essential for the activation of a NF-kappa B homolog in Drosophila [7].
• Furthermore, recent data imply a role for IRAK-1 in tumor necrosis factor receptor (TNFR) superfamily-induced signaling pathways as well [8].
• We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation [9].

Biological context of IRAK1

• We also demonstrate that Akt activity is necessary for IL-1-dependent NF-kappaB transactivation, since a kinase-defective mutant of Akt impairs IRAK2- and MyD88-dependent, but not IRAK1-dependent, NF-kappaB activity, as monitored by a gene reporter assay [10].
• We define sequential phosphorylation steps in IRAK-1, which are, in vitro, autophosphorylation [11].
• Thus, decreased TLR4-MyD88 complex formation with subsequent impairment of IRAK-1 activity may underlie the LPS-tolerant phenotype [12].
• Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation [13].
• This mechanism of tolerance induction which serves to mitigate excessive and potentially harmful inflammatory reactions appears to be due partly to fimbria-induced downregulation of the expression of interleukin-1 receptor-associated kinase-1 (IRAK-1), an important signaling intermediate of the TLR pathway [14].

Anatomical context of IRAK1

• Significantly, the inhibition of Hsp90 in macrophages resulted in the destabilization and degradation of IRAK-1 but not IRAK-4 [15].
• However, exposing monocytes to a nitric oxide (NO) donor inhibits the activity of IRAK-1 and its molecular interaction with TNF receptor associated factor-6 (TRAF6) [16].
• Lipopolysaccharide (LPS) signaling leading to nuclear factor-kappaB activation in mononuclear phagocytes involves interleukin-1 receptor-associated kinase (IRAK), which is rapidly activated after exposure to agonist [17].
• Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression [18].
• Using a variety of dominant negative constructs, we have identified a role for MyD88 and interleukin-1 receptor-associated kinase-1 (IRAK-1) in mediating LPS pro-apoptotic signaling in human endothelial cells [19].

Associations of IRAK1 with chemical compounds

• Strikingly, such LTA-adapted cells still respond to LPS stimulation of TLR4 with rapid activation and degradation of IRAK1, and robust IL-1beta/TNF-alpha production [20].
• Third, IRAK-1 autophosphorylates several times in the proline-, serine-, and threonine-rich ProST region between the N-terminal death domain and kinase domain [11].
• Substitution of Thr209 by alanine results in a kinase-inactive IRAK-1 [11].
• Tumor necrosis factor associated factor-6 (TRAF6) is an ubiquitin ligase that is activated by ubiquitination and a signaling intermediate between IRAK1 and IkappaBalpha [21].
• Identification of threonine 66 as a functionally critical residue of the interleukin-1 receptor-associated kinase [22].

Physical interactions of IRAK1

• Formation of the signaling IL-1 receptor complex results in the activation and hyperphosphorylation of IRAK-1, which leads to a pronounced shift of its apparent molecular mass in gel electrophoresis [11].
• The interleukin-1 receptor-associated kinase 1 (IRAK-1) is an important adapter in the signaling complex of the Toll/interleukin-1 (IL-1) receptor family [11].
• IL-8-induced NF-kappaB activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells [23].

Enzymatic interactions of IRAK1

• In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1 [24].
• The recent characterization of an IL-1 receptor associated kinase (IRAK) and a continuous molecular path between this kinase and that which directly phosphorylates IkappaB would seem to all but close the basic understanding of IL-1 receptor signal transduction [25].
• IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation [26].

Regulatory relationships of IRAK1

• These results suggest that acute alcohol attenuates TLR4-induced inflammation via inhibition of IRAK-1 and ERK1/2 kinases and increases in IRAK-monocyte levels in monocytes [27].
• Taken together, these results indicate a novel regulatory mechanism for IL-1beta signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1beta-induced NF-kappaB activation through interference with the coupling of IRAK1 to MyD88 [28].
• Truncated IRAK-4 proteins constitutively interacted more strongly with MyD88 and blunted IL-1-induced recruitment of IRAK-1 and MyD88 to the IL-1R [29].
• Furthermore, MyD88Delta inhibited NE-induced IRAK degradation [30].
• However, neither TNF-alpha nor IL-1beta induced IRAK degradation or stimulated TNF-alpha or TxB2 production in naive cells [31].

Other interactions of IRAK1

• In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappaB pathways, the CTAR2-mediated NF-kappaB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement [32].
• Hyperphosphorylation of this region leads to dissociation of IRAK-1 from the upstream adapters MyD88 and Tollip but leaves its interaction with the downstream adapter TRAF6 unaffected [11].
• LPS induced the association of MyD88 with TLR4 and increased IRAK-1 activity in medium-pretreated cells [12].
• This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation [33].
• Concomitant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2 complex [34].

Analytical, diagnostic and therapeutic context of IRAK1

• In this paper, we report that IRAK2 and MyD88, but not IRAK1, interact physically with Akt, as demonstrated by co-immunoprecipitation and pull-down experiments [10].
• The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis [13].
• In this large case-control study, we tested two hypotheses: (a) sequence variants in IRAK1 and IRAK4 are associated with prostate cancer risk and (b) sequence variants in IRAK1/4 and TLR1-6-10 interacts and confers a stronger risk to prostate cancer [2].
• METHODS: The expression of TLR2-5, MD-2, MyD88, and IRAK1 was examined in human liver tissue and cultured BECs by immunohistochemistry or reverse transcription polymerase chain reaction [35].
• Association of IL-1 receptor-associated kinase (IRAK) with MyD88 was studied by co-immunoprecipitation and Toll-like receptor 4 (TLR4) determined by FACS scan and Western blotting [36].

References