Regulation of innate immune signaling by IRAK proteins

Abstract

The Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) families are of paramount importance in coordinating the early immune response to pathogens. Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). This signaling adaptor forms the scaffold of the myddosome, a molecular platform that employs IL-1R-associated kinase (IRAK) proteins as main players for transducing signals. These kinases are essential in controlling gene transcription by regulating myddosome assembly, stability, activity and disassembly. Additionally, IRAKs play key roles in other biologically relevant responses such as inflammasome formation and immunometabolism. Here, we summarize some of the key aspects of IRAK biology in innate immunity.

Keywords: IL-1R; IRAK; TLR; cell signaling; inflammation; innate immunity.

Figure 1

Pro-inflammatory responses are coordinated by the myddosome. The myddosome is a supramolecular signaling complex assembled upon dimerization of IL-1Rs and most TLRs (except TLR3), and is composed of MyD88, IRAK4, IRAK1 and/or IRAK2, in addition to TRAF6. Its activity coordinates the inflammatory response by activating NLRs, modulating metabolic responses, and regulating gene transcription via activation of transcription factors such as NF-κB, AP-1, IRF5, and IRF7.

Figure 2

Organization of human IRAK proteins. IRAK proteins contain a death domain (DD), ProST domain, kinase domain (inactive in IRAK-M) and a C-terminal domain (absent in IRAK4). IRAK1 has two putative PEST sequences in its ProST region. IRAK-M contains a guanylate cyclase (GC) center in its kinase domain. The C-terminal domain contains up to three TRAF6 binding motifs (TBMs), and is absent in IRAK4.

Figure 3

Steps of myddosome assembly. Dimerization of IL-1R or TLRs (except TLR3) leads to conformational changes in their cytoplasmic TIR domains, allowing TIR-TIR interactions with molecules of MyD88 to occur, either directly or via Mal dimers. This leads to formation of small and unstable MyD88 oligomers, which grow if receptor activation is sustained. After reaching a certain size threshold, MyD88 oligomers are stabilized by IRAK4. Interactions with MyD88 allows IRAK4 to trans-autophosphorylate and recruit IRAK1. Next, IRAK1 is activated by phosphorylation events mediated by IRAK4, and then further activated by auto-phosphorylation in its ProST regions, allowing signaling to occur.

Figure 4

IRAK2 is essential for late-phase TLR signaling. TLR activation at the membrane triggers the sequential recruitment of Mal, MyD88, IRAK4, IRAK1 and TRAF6, forming the myddosome. These early membrane-bound complexes are short-lived and detectable only within minutes of stimulation. Sustained TLR stimulation leads to formation of cytosolic myddosomes containing IRAK2.

Figure 5

Myddosome signaling is regulated at nearly every step. Signaling through the myddosome leads to transcription of negative regulators such as SOCS1, iNOS, IRAK-M and A20. Proteasomal degradation of components such as Mal (controlled by SOCS1), MyD88 (controlled by A20 and NRDP1, in addition to SPOP in HSC), IRAK1 (controlled by β-TrCP), and TRAF6 (triggered by IRAK1) are likely involved in myddosome disassembly and signal termination. IRAK-M antagonizes the myddosome by inhibiting the binding between IRAK1 and TRAF6, besides stimulating A20 expression. Production of NO by eNOS and iNOS leads to S-Nitrosylation of MyD88, inhibiting signal transduction.