Abstract. Toll-like receptors (TLRs) recognize conserved pathogen-associated molecular patterns (PAMPs) and activate the defensive innate immune signaling

AbstractToll-like receptors (TLRs) recognize conserved pathogen-associated molecular patterns (PAMPs) and activate the defensive innate immune signaling networks. The adaptor protein myeloid differentiation primary response gene 88 (MyD88) functions as a critical scaffold downstream of almost all TLRs, orchestrating the assembly of a supramolecular organizing center (SMOC) called the myddosome. Here, we mapped the interactomes of endogenous MyD88 in mouse macrophages stimulated with four TLR ligands: lipopolysaccharide (LPS), Pam3CysSerLys4 (Pam3CSK4), R848 (resiquimod), and Poly(I:C) (a MyD88-independent negative control) across five time points (0, 10, 30, 60, and 120 min) using 3-plex stable isotope labeling by amino acids in cell culture (SILAC) and affinity purification-mass spectrometry (AP-MS). The results revealed a dynamic, agonist-specific MyD88 interactome, capturing canonical myddosome components (IRAK1, IRAK2, and IRAK4) and novel noncanonical signaling partners, including double-stranded RNA-dependent protein kinase (Eif2ak2/PKR), transactivation response RNA-binding protein 2 (Tarbp2/TRBP), and protein activator of PKR (Prkra/PACT). Downstream validation using targeted coimmunoprecipitation and pharmacological inhibitors confirmed that these noncanonical RNA-binding adaptors are recruited to the MyD88 niche and modulate downstream transcriptional activation, mRNA stability, and microRNA biogenesis (miR-146a, miR-21). These results highlight the modular plasticity of the myddosome, demonstrating its role as a physical scaffold and a temporal integrator that shapes context-dependent innate immune responses.

Myddosomes, in which MyD88 forms barrel-like scaffold structures for effector protein recruitment and activation, contain proteins that act at all stages and regulate all effector responses of the TLR signalling pathways.

Read the full paper: TLR9–MyD88–TRAF6 signaling mediates mitochondrial DNA–induced systemic inflammatory response after radiofrequency ablation of hepatic hemangioma, with Merlin as a downstream participant

Journal of ethnopharmacology · Tao R, Li X, Ji L, Li Y, Su T, Ma M, Gu F, Yang L, Zang N, Chen C, Liu D, Lin Q.

A Cleveland Clinic research team studying alcohol and the brain discovered a new way that alcohol abuse can cause brain dysfunction and damage: through immune cells called microglia. The research also...

Alcohol’s brain effects are attributed to neurons, leaving microglial functional involvement untested. Paouri, Stanko, et al. show that microglia drive alcohol-induced sedation, motor impairment, and synaptic and neuronal loss through MyD88-dependent perisynaptic extracellular matrix (ECM) disruption. Equivalent neuron-targeted sedation bypassing microglia spares the ECM. Brain ECM loss also marks human alcohol use disorder, identifying a therapeutic target distinct from neuronal interventions.

This study identifies a new step in the evolutionary arms race between host and fungus in the Drosophila brain. The fungus B. bassiana exploits the Toll-1 host response to activate the MyD88 inhibitor...

TRAM is a regulator of myddosome assembly through dissociating MyD88 from the TLR–TIRAP complex to enable myddosome maturation and durable downstream signal transduction.

Lipid nanoparticle–delivered DNA triggers cGAS-dependent innate immunity, limiting transgene persistence and causing hepatotoxicity. Sun and colleagues identify a cGAS–interferon–TREX1 axis that degrades therapeutic DNA and a parallel MyD88-driven inflammatory pathway. Prophylactic dexamethasone or JAK inhibition mitigates toxicity, revealing immunomodulation as a strategy to unlock DNA-based gene therapy.

TRAM is a regulator of myddosome assembly through dissociating MyD88 from the TLR–TIRAP complex to enable myddosome maturation and durable downstream signal transduction.

TRAM is a regulator of myddosome assembly through dissociating MyD88 from the TLR–TIRAP complex to enable myddosome maturation and durable downstream signal transduction.

TRAM is a regulator of myddosome assembly through dissociating MyD88 from the TLR–TIRAP complex to enable myddosome maturation and durable downstream signal transduction.