IRAK4
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.
History
The first IL-1 receptor-associated kinase (IRAK) was observed in 1994 through experiments with murine T helper cell lines D10N and EL-4.[5] Two years later the first experimental member of this family of kinases, IRAK1, was cloned.[6] 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.[7]
IRAK4 was proposed to be the mammalian homolog of the Pelle gene found in
In 2007 it was found that IRAK4 activity was necessary for activating signal pathways which lead to
Protein structure
IRAK4 is a threonine/serine protein kinase made up of 460 amino acids, which contains both a kinase domain and a death domain.[7] Its kinase domain exhibits the typical bilobed structure of kinases, with the N-terminal lobe consisting of a five-stranded antiparallel beta-sheet and one alpha helix. The C-terminal lobe is composed mainly of a number of alpha helices.[9] 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.[10] 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.[9] The protein also contains three auto-phosphorylation sites, each of which when mutated results in a decrease in the kinase activity of IRAK4.[11]
A structure of the autophosphorylation of the
Function, mechanism, signalling pathway
Members of interleukin-1 receptor (Il-1R) and the Toll-like receptor superfamily share an intracytoplasmic Toll-IL-1 receptor (
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
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
Clinical significance
There are three components of evidence that illustrate IRAK4's involvement in TLR signalling. First, IRAK4 is the initial kinase near the TLR receptor to activate downstream effectors such as cytokines and chemokines in the inflammatory cascade.[7] Second, deletion of the IRAK4 gene results in various cytokine response defects and finally, patients with IRAK4 deficiency have displayed defective immunity in response to IL-1, IL-8 and other TLR binding ligands.[16] Considering IRAK4's downstream position of these signalling events, it is an important drug therapy target for various inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases.[17]
Prostate cancer
An important area of research currently being explored[by whom?] is the role the IRAK4 gene may play in the development of prostate cancer. There are several interacting factors that lead to the development of this disease however genetic susceptibility of chronic inflammation has been deemed one of the most important. It has been found that mutations in the IRAK4 gene can lead to dysfunctional TLR signalling and ultimately result in increased innate immune responses and therefore an increased inflammatory response. Over time, this can lead to the onset of prostate cancer.[18]
Melanoma
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.[17]
IRAK4 is higher levels in some lines of melanoma. By reducing IRAK4 activity it may be possible to identify new chemotherapeutic agents to treat patients with advanced melanoma for which no effective treatment is available.[19]
Pancreatic cancer
In a mice model, administering IRAK4 reduced inflammatory signaling, after which T-cells began to attack tumors and immunotherapy became more effective.[20]
Drug target
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.[15] Children with IRAK4 deficiency have been found to have decreased immunity to some specific bacterial infections yet not to viral, parasitic or other microbe infections. However, as these children enter adulthood and maternal antibodies are no longer present, susceptibility to infections becomes a rarity. In one study, no significant bacterial infections were documented in all investigated patients over the age of 14 with IRAK4 deficiency. This may mean that in later stages of life, IRAK4 inhibition could provide benefits against certain diseases while maintaining immunity.[21]
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. As of 2007[update] All potential drugs are in the early preclinical stages of development.[22]
Early-stage clinical trials of an IRAK4 inhibitor had started by 2019.[23] Moreover, IRAK4 protein degraders have recently entered clinical trials, most notably one from Kymera Therapeutics.[24]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000198001 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059883 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ PMID 11960013.
- ^ PMID 17485511.
- ^ PMID 17161373.
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- PMID 17141195.
- PMID 25201411.
- PMID 26628682.
- S2CID 21786295.
- ^ PMID 19689377.
- ^ S2CID 4428621.
- ^ PMID 25479567.
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- PMID 35271824.
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- PMID 17893200.
- ^ Curis, Inc. (2019). "Curis Provides First-Ever Demonstration that Targeting IRAK4 in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma Results in Anti-Cancer Activity in Ongoing Phase 1 Study". PR Newswire Association LLC.
- S2CID 226249972.
External links
- IRAK4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: Q9NWZ3 (Human Interleukin-1 receptor-associated kinase 4) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: Q8R4K2 (Mouse Interleukin-1 receptor-associated kinase 4) at the PDBe-KB.
