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IRAK4

Official Full Name
interleukin 1 receptor associated kinase 4
Organism
Homo sapiens
GeneID
51135
Background
This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
Synonyms
IPD1; IMD67; REN64; IRAK-4; NY-REN-64;
Bio Chemical Class
mRNA target
Protein Sequence
MNKPITPSTYVRCLNVGLIRKLSDFIDPQEGWKKLAVAIKKPSGDDRYNQFHIRRFEALLQTGKSPTSELLFDWGTTNCTVGDLVDLLIQNEFFAPASLLLPDAVPKTANTLPSKEAITVQQKQMPFCDKDRTLMTPVQNLEQSYMPPDSSSPENKSLEVSDTRFHSFSFYELKNVTNNFDERPISVGGNKMGEGGFGVVYKGYVNNTTVAVKKLAAMVDITTEELKQQFDQEIKVMAKCQHENLVELLGFSSDGDDLCLVYVYMPNGSLLDRLSCLDGTPPLSWHMRCKIAQGAANGINFLHENHHIHRDIKSANILLDEAFTAKISDFGLARASEKFAQTVMTSRIVGTTAYMAPEALRGEITPKSDIYSFGVVLLEIITGLPAVDEHREPQLLLDIKEEIEDEEKTIEDYIDKKMNDADSTSVEAMYSVASQCLHEKKNKRPDIKKVQQLLQEMTAS
Open
Approved Drug
0
Clinical Trial Drug
6 +
Discontinued Drug
0

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Detailed Information

IRAK4 is one of four members of the interleukin-1 receptor-associated kinase (IRAK) family, together with IRAK1, IRAK2, and IRAK3 (IRAKM), forming this important family of serine/threonine kinases. IRAK4 is the most important member of this family, consisting of 460 amino acids with a molecular weight of approximately 52 kDa.

IRAK4 has several key domains:

  • N-terminal death domain (DD): responsible for interactions with other proteins containing DD, such as MyD88
  • Proline/serine/threonine (ProST) domain: involved in protein-protein interactions
  • Kinase domain (KD): possesses catalytic activity, including an ATP binding site
  • Unlike other IRAK members, IRAK4 lacks a C-terminal domain (CD)

The kinase domain of IRAK4 has a typical bilobed structure with the active site in between. Its unique "gatekeeper" residue Tyr262 forms a hydrogen bond with Glu233, maintaining IRAK4's active conformation. Additionally, Val263, Tyr264, and Met265 form a hinge region, which is important for inhibitor design.

Role of IRAK4 in IL-1R/TLRs Signaling Pathway

IRAK4 plays a central role in the interleukin-1 receptor (IL-1R) and Toll-like receptor (TLRs) signaling pathway. When IL-1R/TLRs are activated by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), they recruit MyD88 through their TIR domain, promoting IRAK4 dimerization, trans-autophosphorylation, and activation, forming the myddosome complex.

In this process, IRAK4 has dual functions:

1. Kinase activity: phosphorylating downstream proteins, including IKKs and JNK/p38

2. Scaffolding function: promoting the assembly of the myddosome complex, providing a platform for protein-protein interactions

IRAK4 activation initiates a series of cascade reactions:

  • IRAK1 and IRAK2 are recruited and activated
  • Activated IRAK1 binds to TRAF6
  • Further activation of TAK1 and IKK complex
  • Activation of NF-κB and MAPK signaling pathways
  • Promotion of pro-inflammatory factors (IL-1, IL-6, IL-8, etc.)

These processes ultimately lead to inflammatory responses, playing important roles in immune defense and tissue damage.

IRAK4 and Autoimmune Diseases

IRAK4 plays important roles in the pathogenesis of various autoimmune diseases:

Figure 1: Diagram illustrating the role of the IL-1R/TLR-IRAK4-NF-κB signaling pathway in autoimmune diseases and cancer development. Figure 1. The role of IL-1R/TLRseIRAK4eNF-kB signal pathway in the development of autoimmune diseases and cancer. (Feng Y, et al., 2024)

Rheumatoid Arthritis (RA): In RA, TLRs on monocytes/macrophages in synovial fluid are activated by endogenous molecules, inducing NF-κB to secrete pro-inflammatory factors. Studies have shown that IRAK4 knockout mice (IRAK4-KO) exhibit reduced production of NF-κB induced by IL-1β, demonstrating that IRAK4 is involved in the activation of NF-κB downstream of IL-1β signaling.

Systemic Lupus Erythematosus (SLE): Activation of TLR2/4 and TLR7/9 signaling pathways can lead to the release of pro-inflammatory cytokines and the production of autoantibodies, which deposit in various tissues, causing inflammation and tissue damage. The IRAK4-targeting drug BMS-986126 has shown potential to alleviate SLE symptoms in preclinical studies.

Alcoholic Liver Disease (ALD): Increased intestinal permeability after alcohol consumption leads to the accumulation of TLR ligand LPS in the liver, which is recognized by IL-1R/TLRs on Kupffer cells, forming a complex that activates NF-κB. Studies have found that phosphorylated IRAK4 levels are elevated in ALD patients, and IRAK4 inhibitors can alleviate alcohol-induced liver injury.

Additionally, research on inflammatory bowel disease, psoriasis, neuroinflammatory diseases, and Sjögren's syndrome has also highlighted the importance of IRAK4 as a therapeutic target.

IRAK4 and Cancer

IRAK4 inhibitors have been designed for the treatment of various cancers:

Activated B-cell Diffuse Large B-cell Lymphoma (ABC-DLBCL): In ABC-DLBCL cells, the L265P mutation of MyD88 leads to non-dependent oligomerization of the myddosome complex, activating IRAK4 and further inducing NF-κB activation, promoting B-cell proliferation and survival.

Myelodysplastic Syndrome (MDS): Abnormal or enhanced signaling of the TLR4-IRAK4-NF-κB pathway leads to hematopoietic system disorders. In MDS patients, TLRs are overexpressed/mutated, leading to downstream IRAK4 overexpression/hyperactivation, affecting hematopoietic stem and progenitor cell (HSPC) function and leading to MDS development.

Other IRAK4-related tumors include chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), as well as colon, breast, and lung cancers.

IRAK4-Targeted Drug Development Strategies

Currently, there are three main design directions for IRAK4-targeted drug development:

1. Small Molecule Inhibitors

The failure of Zimlovisertib and Zabedosertib in treating atopic dermatitis highlights the complexity of the disease. Atopic dermatitis involves intricate inflammatory interactions in the skin, where IRAK4 plays a vital role in amplifying inflammation. Traditional small-molecule inhibitors are ineffective in addressing IRAK4's scaffolding function, limiting their therapeutic potential. However, AstraZeneca's AZD6793 has shown promise in treating COPD by inhibiting IRAK4, reducing inflammation, and improving lung function, as COPD relies less on IRAK4's scaffolding function.

2. Multi-target Drugs

Multi-target drugs are emerging as a potential solution to drug resistance in hematological malignancies. FLT3/IRAK4 dual-target inhibitors help overcome resistance in acute myeloid leukemia (AML) by blocking both FLT3 and IRAK4 signaling pathways, preventing tumor proliferation. Similarly, BTK/IRAK4 inhibitors address resistance in B-cell malignancies by inhibiting both the BCR/BTK and MyD88/IRAK4 pathways. Additionally, Rigel's R289, a dual IRAK1/4 inhibitor, is progressing in clinical trials for low-risk myelodysplastic syndrome (LR-MDS), showing promise in reducing inflammatory cytokines and improving patient outcomes.

3. PROTAC Technology

PROTAC technology offers a revolutionary approach to IRAK4-targeted drug development, shifting from inhibition to degradation. PROTAC molecules enable the degradation of IRAK4, blocking its kinase activity and eliminating its scaffolding function. Sanofi and Kymera's KT-474, an oral IRAK4 protein degrader, has shown positive results in clinical trials, demonstrating IRAK4 degradation and reductions in inflammatory biomarkers in patients with immuno-inflammatory diseases. This breakthrough could potentially transform treatments for conditions like atopic dermatitis and hidradenitis suppurativa, with Phase 2 trials ongoing.

References

  1. Feng Y, Chen C, Shao A, et al. Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta Pharm Sin B. 2024 Dec;14(12):5091-5105.
  2. Kang C, Li X, Liu P, et al. Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis. Front Immunol. 2023 Oct 17;14:1276512.
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