IRAK1
Description
The IRAK1 (interleukin 1 receptor associated kinase 1) is a protein-coding gene located on chromosome X.
Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.
== Structure == IRAK-1 contains an N-terminal death domain (DD), a ProST domain, a centrally located kinase domain, and a C-terminal domain. The DD on IRAK-1 acts as an interaction platform for other DD-containing protein, most notably the adaptor protein myeloid differentiation factor 88, MyD88. The proST domain contains serine, proline, and threonine amino acid residues and is used to facilitate IRAK-1 interaction with other IRAK family members or proteins. For example, auto-phosphorylation may occur multiple times in the ProST domain, which allows IRAK-1 to dissociate from the MyD88 bound to the DD while maintaining interactions with downstream proteins such as TNF receptor-associated factor 6 (TRAF-6) to initiate further pathway signaling. Moreover, IRAK-1 contains an invariant lysine within the centrally located kinase domain. The invariant lysine acts as a binding site for ATP and a mediator for catalytic function and kinase activity.
IRAK1, a serine/threonine-protein kinase, plays a pivotal role in the initiation of the innate immune response against invading pathogens. It is involved in both Toll-like receptor (TLR) and IL-1R signaling pathways. Upon TLR activation, IRAK1 is rapidly recruited by MYD88 to the receptor-signaling complex. This association triggers IRAK1 phosphorylation by IRAK4, followed by autophosphorylation and activation of its kinase activity. IRAK1 then phosphorylates E3 ubiquitin ligases, the Pellino proteins (PELI1, PELI2, and PELI3), promoting pellino-mediated polyubiquitination of IRAK1 itself. Subsequently, 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. MAP3K7/TAK1 subsequently activates IKKs (CHUK/IKKA and IKBKB/IKKB), ultimately leading to NF-kappa-B nuclear translocation and activation. Alternatively, IRAK1 can phosphorylate TIRAP, promoting its ubiquitination and subsequent degradation. It also phosphorylates interferon regulatory factor 7 (IRF7), inducing its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which place the cell in an antiviral state. When sumoylated, IRAK1 translocates to the nucleus and phosphorylates STAT3.
IRAK1 is also known as IRAK, pelle.
