InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: IRAK4

Summary

InnateDB Protein

IDBP-372638.4

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

IRAK4

Protein Name

interleukin-1 receptor-associated kinase 4

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000390651

InnateDB Gene

IDBG-28022 (IRAK4)

Protein Structure

UniProt Annotation

Function

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor- signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. 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, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269PubMed:11960013, ECO:0000269PubMed:12538665, ECO:0000269PubMed:15084582, ECO:0000269PubMed:17217339, ECO:0000269PubMed:17337443, ECO:0000269PubMed:17997719, ECO:0000269PubMed:20400509}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:21325272}.

Disease Associations

Recurrent isolated invasive pneumococcal disease 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. {ECO:0000269PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry.IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269PubMed:12637671, ECO:0000269PubMed:12925671}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 54 experimentally validated interaction(s) in this database.
They are also associated with 8 interaction(s) predicted by orthology.

Experimentally validated
Total	54 [view]
Protein-Protein	54 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	8 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000287	magnesium ion binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005149	interleukin-1 receptor binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups

Biological Process

GO:0001816	cytokine production
GO:0002224	toll-like receptor signaling pathway
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0006468	protein phosphorylation
GO:0007165	signal transduction
GO:0007254	JNK cascade
GO:0019221	cytokine-mediated signaling pathway
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0034146	toll-like receptor 5 signaling pathway
GO:0034162	toll-like receptor 9 signaling pathway
GO:0034166	toll-like receptor 10 signaling pathway
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0045087	innate immune response (InnateDB)
GO:0048661	positive regulation of smooth muscle cell proliferation

Cellular Component

GO:0005615	extracellular space
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0010008	endosome membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR011029 Death-like domain
IPR017428 Interleukin-1 receptor-associated kinase 4
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714

PRINTS

PR00109

PIRSF

PIRSF038189

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References