MyD88-Family Adaptors: Compartmentalised Signalling and Non-Immune Functions

The myeloid differentiation primary response protein 88 (MyD88) family of Toll/interleukin-1 receptor (TIR) domain-containing adaptor proteins constitutes a central signalling hub that integrates innate immune sensing with tissue-specific stress responses. This family comprises five mammalian members: MyD88, TIRAP/MAL, TRIF/TICAM-1, TRAM/TICAM-2 and SARM1 (also known as MyD88-1 through MyD88-5). While these adaptors are classically defined by their roles in immune and haematopoietic cells, accumulating genetic and mechanistic evidence demonstrates critical, cell-intrinsic functions in non-immune tissues. Canonical MyD88 signalling assembles IRAK-containing complexes to activate NF-κB and MAPK pathways, whereas TIRAP and TRAM function as sorting adaptors that impose spatial and receptor specificity. TRIF mediates MyD88-independent interferon programs downstream of Toll-like receptor (TLR)-3 and internalised TLR-4. Beyond immunity, MyD88-family signalling regulates epithelial barrier integrity, hepatic metabolic homeostasis, skeletal muscle metabolism and atrophy, endothelial permeability, renal injury responses and neuronal degeneration. Notably, SARM1 represents a functionally divergent family member whose TIR domain acts as an intrinsic NAD⁺ hydrolase driving axonal degeneration. Here, we synthesise structural, genetic and cell-specific studies to highlight how compartmentalised adaptor usage and domain-specific mechanisms generate context-dependent signalling outcomes across immune and non-immune tissues. These insights redefine MyD88-family adaptors as modular regulators of tissue physiology and disease, with implications for targeted therapeutic intervention.