IRAK4

IRAK4 is serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. IRAK4 is involved in Toll-like receptor (TLR) and IL-1R signaling pathways. IRAK4 is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. IRAK4 phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. IRAK4 phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, IRAK4 phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. IRAK4 phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.

IRAK4 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Interleukin-1 Receptor-Associated Kinase (IRAK)>>IRAK4/IRAK-4

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Interleukin-1 Receptor-Associated Kinase (IRAK)>>IRAK4/IRAK-4

Signal Transduction>>Translational Regulator>>IRAK4/IRAK-4

IRAK4 Alternative Names

IRAK4, IRAK-4, IPD1, NY-REN-64, REN64 [Homo sapiens]

Irak4, IRAK-4, 8430405M07Rik, 9330209D03Rik, NY-REN-64 [Mus musculus]

Summaries for IRAK4

Entrez Gene summary for IRAK4:

This IRAK4 gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. IRAK4 is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

OMIM - description for IRAK4:

Interleukin-1 receptor (see IL1R; 147810)-associated kinases (e.g., IRAK1; 300283) are important mediators in the signal transduction of Toll-like receptor (TLR, e.g., TLR4; 603030) and IL1R family members, collectively referred to as TIRs. IRAK4 functions in this signal transduction pathway (Li et al., 2002).

Wikipedia summary for IRAK4:

IRAK4 (interleukin-1 receptor-associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. IRAK4 also supports signaling from T-cell receptors.
Animals without IRAK4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge.

Human IRAK4 Protein General Information

 

• Protein names: Interleukin-1 receptor-associated kinase 4, Short name=IRAK-4
• Sequence length: 460 AA.
• Cofactor: Magnesium.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Sequence similarities: IRAK4 belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. IRAK4 contains 1 death domain. IRAK4 contains 1 protein kinase domain.
• Post-translational modification: Phosphorylated
• Subunit structure: IRAK4 associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Interacts with IL1RL1.
• Subcellular location: Cytoplasm
• Tissue specificity: Kinetic parameters:
  KM=650 µM for ATP (at pH 7.5) KM=1100 µM for substrate (at pH 7.5)
• Biophysicochemical properties: Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.

General information above from UniProt

Function for IRAK4 Protein

UniProtKB:

IRAK4 is serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. IRAK4 is involved in Toll-like receptor (TLR) and IL-1R signaling pathways. IRAK4 is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. IRAK4 phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. IRAK4 phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, IRAK4 phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. IRAK4 phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.

Genatlas:

• IRAK4 is central element in the early signal transduction of Toll/IL1R (TIR) upstream of IRAK1
• IRAK4 is required for various responses induced by IL-1R and Toll-like receptor signals
• IRAK4 is required for the optimal transduction of IL1-induced signals, including the activation of IRAK1, NF-kappaB, and JNK, and the maximal induction of inflammatory cytokines
• IRAK4 plays a critical role in IL1 receptor (IL1R)/TLR7-mediated induction of inflammatory responses
• IRAK4 initiates a cascade of signaling events eventually leading to induction of inflammatory target gene expression (Pubmed 17890055)
• IRAK4 plays an important role in innate and adaptive immune responses (Pubmed 18286567)
• its kinase activity is required for IRAK4-dependent signaling in innate and adaptive immunity (Pubmed 18286567)
• protein kinases that mediate signaling by Toll/IL1/Plant R (TIR) domain-containing receptors including the IL-1, IL-18, and Toll-like receptors (TLRs)(Pubmed 19181383)
• its non-kinase functions are essential in cells, whereas the kinase activity of IRAK4 appears redundant with that of IRAK1 (Pubmed 19181383)
• IRAK4 has a kinase activity that is critical for development of atherosclerosis
• IRAK4 has an ability to induce the degradation of IRAK1 in addition to its role as an activator of IRAK1 (Pubmed 18079163)
• IRAK4 induces the degradation of IRAK1 in a proteosome-independent manner (Pubmed 20400509)
• MYD88 and the associated kinases IRAK1 and IRAK4 are essential for activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) survival (Pubmed 21179087)

Homology for human IRAK4

• ortholog to Drosophila pelle

Phenotype Information for IRAK4

• Gene/Locus: IRAK4, REN64, IPD1
• Phenotype: Invasive pneumococcal disease, recurrent isolated, 1
  IRAK4 deficiency

Phenotype Information for IRAK4 from OMIM (Online Mendelian Inheritance in Man)