Signalling adaptors used by Toll-like receptors: an update.
Research into the five Toll/IL1 receptor (TIR) adaptor proteins involved in innate immunity continues to advance. Here we outline some of the more recent findings. MyD88 has a key role in signalling by the IL1 receptor complex and TLRs. However, a MyD88-independent pathway of IL1beta signalling in neurons has been described which involves the protein kinase Akt, and which has an anti-apoptotic effect. This pathway may also be important for the mechanism whereby Alum exerts its adjuvant effect since this depends on IL1beta but is MyD88-independent. MyD88 is also involved in tumourigenesis in models of hepatocarcinoma and familial associated polyposis (FAP); negative regulation of TLR3 signalling and in PKCepsilon activation. The adaptor Mal is regulated by phosphorylation and caspase-1 cleavage. A variant form of Mal in humans termed S180L confers protection in multiple infectious diseases. TRAM is controlled by myristoylation and phosphorylation and the localisation of TRAM with TLR4 to endosomes is required for activation of IRF3 and induction of IFNbeta. Finally SARM has been shown to regulate TRIF and also appears to be involved in neuronal injury mediated by oxidative stress in mouse neurons. These advances confirm the importance for the TIR domain-containing adapters in host defence and inflammation.
Kenny
Elaine F
EF
School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. kennyef@tcd.ie
O'Neill
Luke A J
LA
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D051186:Armadillo Domain Proteins / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology; D011992:Endosomes / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051186:Armadillo Domain Proteins; D020170:Caspase 1; D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D051744:Protein Kinase C-epsilon; D017472:Receptors, Interleukin-1; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C435689:SARM1 protein, human; C476286:Ticam1 protein, mouse; C480228:TICAM2 protein, human; C434984:TIRAP protein, human; C495345:TLR4 protein, human