IRAK1

What is IRAK1 protein?

The Interleukin-1 Receptor-Associated Kinase 1, also known as IRAK1 protein, is a critical player in the innate immunity and a key component of the signaling pathway of the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs).

In the quest to gain a thorough knowledge of mammalian Toll-like receptor signaling, IRAK1 was discovered by the Cao and Dixon research team in 1996. It was identified as a IL-1R-associated protein kinase that plays a crucial role in normal immune responses. This finding bridged the gap in understanding the molecular mechanisms underpinning pathogen recognition and the subsequent immune response.

Gene Locus and Protein Structure

IRAK1 gene is located on the X Chromosome's long arm at the position Xq28, an area notorious for containing sequences implicated in debilitating genetic disorders such as Hemophilia A and B, and G6PD deficiency.

The IRAK1 protein is composed of 712 amino acids and has a molecular mass of about 78kDa. It is structurally composed of a central kinase domain, an N-terminal Death Domain (DD), and a C-terminal domain. The DD is used for interactions with MyD88, an adapter protein, facilitating downstream signaling events.

Functions of IRAK1 Protein

One of the primary roles of the IRAK1 protein is its involvement in immunity-related signal transduction pathways. Upon the recognition of microbial components by TLRs or IL-1R, IRAK1 is recruited to the receptor complexes, leading to its activation. This activation initiates a signal transduction cascade resulting in the activation of certain transcription factors like NF-κB and AP-1, which in turn produce a range of pro-inflammatory cytokines.

Additionally, IRAK1 protein also influences adaptive immunity. Recent studies reveal that IRAK1 indirectly modulates adaptive immune system by steering the polarization of helper T cells.

IRAK1 Protein Related Signal Pathway

IRAK1 participates in the TLR and IL-1R signaling pathways. Following a pathogen's invasion, TLRs and IL-1R recognize distinct microbial components, leading to the recruitment of the adapter molecule MyD88. MyD88 binds to IRAK4 and IRAK1, causing the activation of IRAK1. Activated IRAK1 then dissociates from the receptor complex and associates with the E3 ubiquitin ligase TRAF6, leading to activation of downstream molecules like MAPK and NF-kB, which catalyze the production of pro-inflammatory cytokines.

IRAK1 Protein Related Diseases

Mutations or dysregulations in IRAK1 signaling have been strongly linked to a multitude of diseases, primarily autoimmune and inflammatory diseases. The abnormal activation of IRAK1 has also been found in a variety of cancers including breast, gastric, and lung cancers, indicating a potentially significant role in tumorigenesis.

IRAK1 has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE patients, a higher level of IRAK1 was observed, leading to inflammation and autoantibody production. IRAK1 has also been recognized as a potential contributor to Alzheimer's disease, as aberrant IRAK1 activity leads to chronic inflammation, a likely factor in Alzheimer's' disease progression.

•  Inflammatory disorders: IRAK1 plays a crucial role in the activation of inflammatory pathways, such as the Toll-like receptor (TLR) signaling pathway. Abnormal IRAK1 activation or expression has been implicated in the pathogenesis of inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
•  Infectious diseases: The TLR signaling pathway, in which IRAK1 is involved, is critical in the immune response against pathogens. Dysregulation of IRAK1 signaling can contribute to susceptibility to various infections, including bacterial, viral, and fungal infections.
•  Cancer: IRAK1 has been linked to the development and progression of several types of cancer. Aberrant IRAK1 activation promotes tumor growth, survival, and invasion by modulating various signaling pathways involved in cell proliferation, apoptosis, and inflammation. IRAK1 overexpression or hyperactivation has been observed in cancers such as breast cancer, lung cancer, colorectal cancer, and pancreatic cancer.

IRAK1 Protein's Applications

Considering the central role of IRAK1 in immune responses and its connection to various diseases, it's regarded as a promising therapeutic target for pharmaceutical interventions. Small-molecule inhibitors targeting IRAK1, such as the FDA-approved drug pacritinib, have shown encouraging results, especially in treating certain types of leukemia.