Disease relevance of IRAK4

• 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 [1].
• More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive [2].
• Pyogenic bacterial infections in humans with IRAK-4 deficiency [3].
• IRAK-4: A New Drug Target in Inflammation, Sepsis, and Autoimmunity [4].
• Two siblings with lethal pneumococcal meningitis in a family with a mutation in Interleukin-1 receptor-associated kinase 4 [5].

High impact information on IRAK4

• Our results indicate that IRAK-4 has an essential role in innate immunity [6].
• IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS) [6].
• We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells [7].
• Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections [8].
• Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype) [8].

Chemical compound and disease context of IRAK4

• Glycine blunts transplantative liver ischemia-reperfusion injury by downregulating interleukin 1 receptor associated kinase-4 [9].

Biological context of IRAK4

• IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness [10].
• However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs [11].
• Our findings suggest synergistic effects between sequence variants in IRAK4 and the TLR 6-1-10 gene cluster [1].
• IRAK-4 as the central TIR signaling mediator in innate immunity [12].
• RESULTS: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation [13].

Anatomical context of IRAK4

• We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-kappaB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4) [14].
• RESULTS: Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8 [15].
• SUMMARY: Antibody- and complement-mediated opsonization, splenic macrophages and interleukin-1 receptor associated kinase-4- and nuclear factor kappaB-mediated immune responses are crucial for protective immunity to S. pneumoniae [16].

Associations of IRAK4 with chemical compounds

• The structures reveal that IRAK-4 has a unique tyrosine gatekeeper residue that interacts with the conserved glutamate from helix alphaC [17].
• Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a serine/threonine kinase that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs) [17].
• Crystal Structures of IRAK-4 Kinase in Complex with Inhibitors: A Serine/Threonine Kinase with Tyrosine as a Gatekeeper [17].
• Conclusion: Glycine can attenuate hepatic I/RI by downregulating IRAK-4 to interfere with LPS signal transduction [9].
• Examination of the IRAK-4 DD crystal structure reveals a single manganese ion coordinated to surface residues lysine-21 and aspartate-24 [18].

Regulatory relationships of IRAK4

• We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly [19].
• By directly binding IL-1R-associated kinase (IRAK)-1 and IRAK-4, MyD88 serves as a bridging protein, enabling IRAK-4-induced IRAK-1 phosphorylation [20].

Other interactions of IRAK4

• We have previously shown that double-stranded RNA-triggered, Toll-like receptor 3 (TLR3)-mediated signaling is independent of MyD88, IRAK4, and IRAK [21].
• 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 [22].
• Dominant-negative forms of MyD88 and FADD, but not IRAK-4, reduced the cytocidal activity of the lipoproteins [23].
• Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex [24].
• IL-1 induced a strong interaction among the IL-1R, activated IRAK-1, MyD88, and WT, but not mutant, IRAK-4 [24].

Analytical, diagnostic and therapeutic context of IRAK4

• In an attempt to discover novel signal transducers in TIR signaling, we identified human Pellino2 as an interaction partner of IRAK4 [25].
• 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 [1].
• However, glycine, which led to improved survival rate and liver function, significantly alleviated liver parenchyma cell damage by downregulating IRAK-4, TNF-alpha expression and NF-kappaB transcriptional activity compared with the control group [9].
• CONCLUSIONS: The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency [15].

References