Адамның IRAK4 гені: иммунитет және қабыну жолдарындағы рөлі

Protein coding gene in humans

IRAK 4 (interleukin 1 receptor associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll like receptors. It also supports signaling from T cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 has important clinical applications. Animals without IRAK 4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge.

The first IL 1 receptor associated kinase (IRAK) was observed in 1994 through experiments with murine T helper cell lines D10N and EL 4. Two years later the first experimental member of this family of kinases, IRAK1, was cloned. In 2002, through database searches at the National Center for Biotechnology Information in an attempt to recognize novel members of the IRAK family, a human cDNA sequence which encoded a peptide sharing significant homology with IRAK1 was identified. This cDNA sequence was found to have five amino acid substitutions compared to IRAK1 and was termed IRAK4. IRAK4 was proposed to be the mammalian homolog of the Pelle gene found in Drosophila melanogaster and was proposed to require its kinase activity in order for it to function in activating NF κB. It was also proposed by Li et al. that it might function upstream of other IRAKs and possibly cause a cascade of phosphorylation events through its function as an IRAK1 kinase.

IRAK4 is a threonine/serine protein kinase made up of 460 amino acids, which contains both a kinase domain and a death domain. Also contained within IRAK4's N terminal is an extension of twenty amino acids, which is unique to IRAK4 among kinases, even within the IRAK family. Situated where the two lobes meet is an ATP binding site, which is covered by a tyrosine gatekeeper. Tyrosine as a gatekeeper is believed to be unique to the IRAK family of kinases. A structure of the autophosphorylation of the activation loop has been determined in which the activation loop Thr345 of one monomer is sitting in the active site of another monomer in the crystal (PDB: 4U9A, 4U97).

Members of interleukin 1 receptor (Il 1R) and the Toll like receptor superfamily share an intracytoplasmic Toll IL 1 receptor (TIR) domain, which mediates recruitment of the interleukin 1 receptor associated kinase (IRAK) complex via TIR containing adapter molecules. The TIR IRAK signaling pathway appears to be crucial for protective immunity against specific bacteria but is redundant against most other microorganisms. IRAK4 is considered the “master IRAK” in the mammalian IRAK family because it is the only component in the IL 1/TLR signalling pathway that is absolutely crucial to its functioning. When one of these pathways is stimulated, the cell is triggered to release proinflammatory signals and to trigger innate immune actions. The loss of IRAK4, or its intrinsic kinase activity, can entirely stop signalling through these pathways. IRAK4 is involved in signal transduction pathways stimulated by the cellular receptors belonging to the Toll/Interleukin 1 receptor superfamily. The Toll Like Receptors (TLRs) are stimulated by recognition of pathogen associated molecular patterns (PAMPS), whereas members of the IL 1R family are stimulated by cytokines. Both play an essential role in the immune response. The ligand binding causes conformational changes to the intracellular domain which allows for the recruitment of scaffolding proteins. One of these proteins, MyD88, uses its death domains to recruit, orient, and activate IRAK4. IRAK2 can then be phosphorylated and joins with IRAK4 and MyD88 to form the myddosome complex, which further phosphorylates and recruits IRAK1.]] Central to all of these signalling pathways is the kinase IRAK4. Results show that IRAK4 is a crucial component in an animal's response to IL 1. Animals deficient in this kinase were found to be lacking in the ability to recognize viral and bacterial invaders, and were completely resistant to lethal doses of lipopolysaccharide (LPS).

Another interesting application of the IRAK4 gene was found in a study involving human melanoma patients. This research found that patients with melanin cell tumors displayed an increase in the phosphorylation state of IRAK4. The siRNA inhibition of IRAK4 in mice displayed greater programmed cell death (PCD) and slowed tumor growth.

In a mice model, administering IRAK4 reduced inflammatory signaling, after which T cells began to attack tumors and immunotherapy became more effective.

A common concern with IRAK4 drug therapy or knockdown is if its absence would result in unbearable side effects considering IRAK4 plays an extremely central role in the TLR signalling pathway. The next step in this area of research is the formation of safe IRAK4 inhibitors. There has been modest progress in the development of some potential inhibitors of IRAK4 in which their mechanism works by blocking its tyrosine gated ATP binding site. All potential drugs are in the early preclinical stages of development. Early stage clinical trials of an IRAK4 inhibitor had started by 2019. Moreover, IRAK4 protein degraders have recently entered clinical trials, most notably one from Kymera Therapeutics.