IRAK4

Last updated
IRAK4
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IRAK4 , IPD1, IRAK-4, NY-REN-64, REN64, interleukin 1 receptor associated kinase 4, IMD67
External IDs OMIM: 606883 MGI: 2182474 HomoloGene: 41109 GeneCards: IRAK4
Orthologs
SpeciesHumanMouse
Entrez

51135

266632

Ensembl

ENSG00000198001

ENSMUSG00000059883

UniProt

Q9NWZ3
Q69FE3

Q8R4K2

RefSeq (mRNA)

NM_029926

RefSeq (protein)

NP_084202

Location (UCSC) Chr 12: 43.76 – 43.8 Mb Chr 15: 94.44 – 94.48 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 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. [7] This idea of a cascade of phosphorylation events was supported by a study where an IRAK4 knockout in mice showed a more severe phenotype than other IRAK knockout experiments and signalling through Toll/IL-1 receptor (TIR) is virtually eliminated. [7]

In 2007 it was found that IRAK4 activity was necessary for activating signal pathways which lead to mitogen-activated protein kinases (MAPK), or Toll-like receptor-mediated immune responses (TLR), but was not essential to T-cell Receptor (TCR) signalling as was originally proposed. [8]

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 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). [12] [13]

Function, mechanism, signalling pathway

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. [14] 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. [15]

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. [16] 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. [17] The myddosome complex and IRAK1 recruit and activate TNF receptor-associated factor 6 (TRAF6), a ubiquitin protein ligase. [7] TRAF6 can polyubiquitinate IKK-γ as well as itself, which recruits TGF-β activated kinase 1 (TAK1) in order to activate its ability to phosphorylate IKK-β. These pathways both work to degrade IKKγ, which releases NFκB and free it for translocation into the nucleus. Additionally, TAK1 can activate JNK to induce a MAP kinase pathway which leads to AP-1-induced gene expression. [8] Together, AP-1 and NFκB lead to increased cytokine transcription, adhesion molecule production, and release of second messengers of infection. [17]

Overview of signalling pathway through IRAK4 and the myddosome complex. Signalling of IRAK4.png
Overview of signalling pathway through IRAK4 and the myddosome complex.

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). [16] This is due to IRAK4's function as both a structural protein and as a kinase. Both of these functions are required for the myddosome complex formation. Additionally, IRAK4 has been shown to be absolutely essential in a TLR signalling. IRAK4 deficient mice have a profoundly impaired ability to produce IL-6, TNF-α, and IL-12 in response to TLR ligands. However it is worthy of note that despite its importance to many immune signalling pathways, IRAK4 does not appear to be involved in TCR signalling. [8]

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 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]

Related Research Articles

<span class="mw-page-title-main">Toll-like receptor</span> Pain receptors and inflammation

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">MYD88</span> Protein-coding gene in the species Homo sapiens

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Toll-like receptor 5</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">TRAF6</span> Protein-coding gene in the species Homo sapiens

TRAF6 is a TRAF human protein.

<span class="mw-page-title-main">Toll-like receptor 6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">IRAK1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">IL1RAP</span> Protein-coding gene in the species Homo sapiens

Interleukin-1 receptor accessory protein is a protein that in humans is encoded by the IL1RAP gene.

<span class="mw-page-title-main">TOLLIP</span> Protein-coding gene in the species Homo sapiens

Toll interacting protein, also known as TOLLIP, is an inhibitory adaptor protein that in humans is encoded by the TOLLIP gene.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">Toll-like receptor 11</span>

Toll-like receptor 11 (TLR11) is a protein that in mice and rats is encoded by the gene TLR11, whereas in humans it is represented by a pseudogene. TLR11 belongs to the toll-like receptor (TLR) family and the interleukin-1 receptor/toll-like receptor superfamily. In mice, TLR11 has been shown to recognise (bacterial) flagellin and (eukaryotic) profilin present on certain microbes, it helps propagate a host immune response. TLR11 plays a fundamental role in both the innate and adaptive immune responses, through the activation of Tumor necrosis factor-alpha, the Interleukin 12 (IL-12) response, and Interferon-gamma (IFN-gamma) secretion. TLR11 mounts an immune response to multiple microbes, including Toxoplasma gondii, Salmonella species, and uropathogenic E. coli, and likely many other species due to the highly conserved nature of flagellin and profilin.

<span class="mw-page-title-main">Toll-interleukin receptor</span>

The toll-interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, interleukin-1 receptors, toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins where they are involved in resistance to disease and in bacteria where they are associated with virulence. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt Q99836) and TOLLIP (toll-interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signaling cascades. Some TIR domains have also been found to have intrinsic NAD+ cleavage activity, such as in SARM1. In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Members of the very wide interleukin-1 receptor (IL-1R) family are characterized by extracellular immunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structurally homologous proteins, conserved throughout the species as it was identified from plants to mammals. Proteins of this family play important role in host defence, injury and stress. There are four main groups of TIR domain-containing proteins in animals; Toll-like receptors, Interleukin-1 receptor (IL-1R), cytosolic adaptor proteins and insect and nematode Toll. Each of these groups is involved mainly in host defence; Toll receptors are also involved in embryogenesis.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

An innate immune defect is a defect in the innate immune response that blunts the response to infection. These defects may occur in monocytes, neutrophils, natural killer cells, basophils, mast cells or complement proteins.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.

References

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