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

ABSTRACT

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.