IRAK Family
About IRAK Family
Interleukin-1 receptor-associated kinases (IRAKs) are serine/threonine intracellular kinases that help mediate signaling from Toll-like receptor (TLR) and IL-1 receptor family members (IL-1Rs). TLRs are crucial in the innate immune response to microbial pathogens because of their ability to recognize pathogen-associated molecular patterns (PAMPs). IL-1R and its family members, including IL-18R and IL-33R, are cytokine receptors that initiate and control inflammatory and immune responses. Unregulated TLR or IL-1R activation may lead to pathological conditions ranging from chronic inflammation to the onset of autoimmune disease. Several attempts have been made to modulate TLR/IL-1R responses, including direct blocking of receptor activation and inhibition of downstream signaling pathways.
The IRAK family consists of four members: IRAK1, IRAK2, IRAK3 (IRAKM), and IRAK4. IRAK proteins share similar domain organization, with an N-terminal DD, a ProST domain, a central conserved KD, and a C-terminal domain (except for IRAK4, which lacks the C-terminal domain). The DD is vital for signaling because it interacts with other signaling molecules, such as MyD88. However, IRAK members that lack the DD act as signaling antagonists. IRAK1 is hyperphosphorylated in the ProST region, which is rich in Ser, Pro, and Thr residues. Additionally, the ProST domain contains 2 potential PEST sequences that may facilitate the degradation of IRAK. The central KD contains an activation loop that is important for kinase activity. In recently solved crystal structures, the IRAK4 KDs exhibit structural features of both Ser/Thr and Tyr kinases. Furthermore, IRAK family members have a tyrosine gatekeeper residue at the center of the ATP-binding site. Lastly, the C-terminal end is important for the interaction with TRAF6.
Fig.1 Domain architecture, size, and expression pattern of human IRAK family protein kinases. (Rhyasen G W, et al., 2015)
IRAK proteins consist of an amino-terminal death domain, a ProST domain, a kinase or pseudokinase domain, and C-terminus domain important for TRAF6 interaction.
Mechanism of Action of IRAK Family
Members of the IRAK family are tightly associated with signaling pathways in the Toll/IL-1 receptor (TIR) superfamily, with the IL-1 receptor and Toll-like receptor being the most important activated receptors of the family. Below is a general overview of the mechanism of action of the IRAK family:
- Activation
IRAK family members are phosphorylated upon activation by a receptor (e.g., IL-1 receptor or TLR binding its corresponding ligand), which activates their kinase activity. This leads to the formation of a complex between the IRAK family member and the activated receptor.
- Phosphorylation Cascade
Activated IRAK family members initiate and transmit cellular signals through a phosphorylation cascade. IRAK4 first phosphorylates other IRAK members (e.g., IRAK1 and IRAK2), and then activated IRAK1 or IRAK2 further phosphorylates other proteins in the downstream pathway.
- Activation of The Downstream Pathway
Phosphorylation-activated IRAK family members activate proteins in the downstream pathway, including NF-κB (nuclear factor κB) and MAPKs (mitogen-activated protein kinases), which is a transcription factor associated with gene expression and is involved in inflammation and immune response, while MAPKs are involved in the regulation of biological processes such as cell proliferation, survival, and differentiation.
- Gene Transcription and Inflammatory Response
Activated IRAK family members promote the transcription and translation of related genes through the activation of the transcription factor NF-κB, leading to the production of pro-inflammatory factors and proteins related to immune response. These molecules are involved in the inflammatory response, the onset and progression of some diseases.
- Potential Therapeutic Targets
Due to the key role of the IRAK family in the regulation of immunity and inflammation, they are considered potential targets for the treatment of inflammatory and autoimmune diseases. Researchers are working to develop drugs that interact with the IRAK family to modulate their activity and explore their potential application in the treatment of immune-related diseases.
Fig.2 Toll-like receptor and Il-1R family members activate IRAK signaling. (Jain A, et al., 2014)
Overall, the IRAK family regulates the immune response, inflammatory response, and associated diseases by mediating IL-1 receptor and TLR signaling pathways. These mechanisms are complex and diverse, can involve multiple signaling proteins, and are influenced by negative or positive feedback mechanisms of other molecules in the regulatory network. The specifics may vary depending on cell type, activated receptor, and context.
Functions of IRAK Family
- Activation of Immune Response and Regulation of Downstream Signaling
IRAK family members are involved in the activation of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. They interact with adaptor proteins (e.g. MyD88) in the TLR and IL-1R complexes and are phosphorylated and activated to initiate downstream signaling molecules that regulate immune responses and inflammatory responses. In particular, they interact with the NF-κB (nuclear factor-κB) and MAPK (Mitogen-activated protein kinase) signaling pathways to promote inflammatory factor production and immune cell activation.
- Production of Inflammatory Factors and Activation of Immune Cells
Activation of the IRAK family contributes to the production of inflammatory factors, including tumor necrosis factor (TNF-α), interleukins (IL-6, IL-8, etc.), and interferons (IFN-α, IFN-β, etc.). These inflammatory factors play an important regulatory role in the immune response and inflammatory reactions.
Activation of the IRAK family leads to the activation and proliferation of immune cells. They are involved in regulating the differentiation, proliferation, migration, and activation of immune cells, thereby coordinating and enhancing the immune response.
- Negative Regulation of Immune and Inflammatory Modulation
Some members of the IRAK family, such as IRAK2 and IRAK3 (IRAK-M), are negatively regulated. They inhibit the activity of IRAK1 and IRAK4, limiting the intensity and persistence of inflammatory signals to prevent excessive immune and inflammatory responses.
Available Resources for IRAK Family
The IRAK family plays an important role in immune response and inflammatory regulation. They are involved in the activation of signaling pathways and modulation of downstream effects, regulating the production of inflammatory factors and the activation of immune cells. Abnormal IRAK family function may lead to the development of diseases such as immunodeficiency disorders, inflammatory diseases, and autoimmune diseases. Therefore, it is important to study the function and regulatory mechanism of the IRAK family to gain a deeper understanding of the molecular mechanism of immune and inflammatory regulation and to provide new targets and strategies for the treatment of related diseases. Creative BioMart offers a variety of IRAK-related research products, such as recombinant proteins, cell and tissue lysates, and protein pre-coupled magnetic beads, as well as customizable services and other resources to support your research in the field of IRAKs. The following IRAKs are displayed, click to view all related molecules/targets and research reagents. For further information or to purchase products, please contact us. We are committed to providing the highest quality resources and support for your research to help you succeed.
References:
- Rhyasen G W, Starczynowski D T. IRAK signaling in cancer[J]. British journal of cancer, 2015, 112(2): 232-237.
- Jain A, Kaczanowska S, Davila E. IL-1 receptor-associated kinase signaling and its role in inflammation, cancer progression, and therapy resistance[J]. Frontiers in immunology, 2014, 5: 553.
