Fig. 1: Myddosome signaling.
From: Biological drivers of clinical phenotype in myelofibrosis
Ligand engagement of TIR -domain containing receptors triggers their dimerization and myddosome assembly through recruitment of the TIR-domain containing adaptor protein, MyD88. The N-terminal death domains (DD) of MyD88 proteins interact with the DD-containing, serine/threonine IRAK family kinases to create the active macromolecular protein signaling complex that converges upon IRAK1 transphosphorylation. Phosphorylated IRAK1 dissociates from the myddosome complex to activate the E3-ubiquitin ligase TRAF6 that is responsible for the activation of several transcription factors including NF-kB, AP-1, and interferon (IFN) regulatory factors (IRFs). Collectively, these proteins induce the expression of pro-inflammatory cytokines, IFNs and IFN-stimulated genes (ISGs), components of the NLRP3 inflammasome as well as the anti-inflammatory cytokine IL-10, which serves to quench myddosome signaling. The microRNA, miR-146a, also suppresses myddosome signaling through degradation of IRAK-1, TRAF-6 and TGF-β gene transcripts. IRAK1 also directly phosphorylates STAT3, triggering its nuclear translocation independently of the Janus kinases.
