IRAK4 : interleukin 1 receptor associated kinase 4

Description

The IRAK4 (interleukin 1 receptor associated kinase 4) is a protein-coding gene located on chromosome 12.

The IRAK4 gene provides instructions for making a protein that plays an important role in innate immunity, which is the body's early, nonspecific response to foreign invaders (pathogens). The IRAK-4 protein is part of a signaling pathway that is involved in early recognition of pathogens and the initiation of inflammation to fight infection. In particular, the IRAK-4 protein relays signals from proteins called Toll-like receptors and IL-1 receptor-related proteins. As one of the first lines of defense against infection, Toll-like receptors recognize patterns that are common to many pathogens, rather than recognizing specific pathogens, and stimulate a quick immune response. The IL-1 receptor and related proteins recognize immune system proteins called cytokines that signal the need for an immune response. The resulting signaling pathway triggers inflammation, a nonspecific immune response that helps fight infection.

IRAK4 is a serine/threonine-protein kinase that plays a crucial role in initiating the innate immune response against foreign pathogens. It participates in both Toll-like receptor (TLR) and IL-1R signaling pathways. Upon TLR activation, IRAK4 is recruited by MYD88 to the receptor-signaling complex, forming the Myddosome alongside IRAK2. It then phosphorylates IRAK1, activating its kinase activity and inducing intensive autophosphorylation of IRAK1. IRAK4 also phosphorylates E3 ubiquitin ligases, the Pellino proteins (PELI1, PELI2, and PELI3), promoting pellino-mediated polyubiquitination of IRAK1. The ubiquitin-binding domain of IKBKG/NEMO subsequently binds to polyubiquitinated IRAK1, bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. This leads to MAP3K7/TAK1 activating IKKs (CHUK/IKKA and IKBKB/IKKB), ultimately triggering NF-kappa-B nuclear translocation and activation. Alternatively, IRAK4 can phosphorylate TIRAP, promoting its ubiquitination and subsequent degradation. It also phosphorylates NCF1, regulating NADPH oxidase activation following LPS stimulation, suggesting a similar mechanism during microbial infections.

IRAK4 is also known as IMD67, IPD1, IRAK-4, NY-REN-64, REN64.

Associated Diseases

Comprehensive carrier screening

WES Whole Exome Sequencing

Clinical Exome Sequencing