IRAK4

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 (PubMed:17878374). 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.

Involvement in disease

Immunodeficiency 67

IMD67

An autosomal recessive primary immunodeficiency characterized by recurrent, life-threatening systemic and invasive bacterial infections beginning in infancy or early childhood.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylated.

Sequence Similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

Cellular localization

• Cytoplasm

Alternative names

Interleukin-1 receptor-associated kinase 4, IRAK-4, Renal carcinoma antigen NY-REN-64, IRAK4

Database links

swissprot:Q9NWZ3 omim:606883 entrezGene:51135

Other research areas

• Immuno-oncology