title: Different dimerisation mode for TLR4 upon endosomal acidification?
abstract: TLR4 is unique among pathogen-recognition receptors in that it initiates different pathways in different cellular locations. Binding of a bridging factor, Mal, allows recruitment of an adapter protein, MyD88, at the plasma membrane, which leads to the production of proinflammatory cytokines. Upon internalization, TLR4 uses a different bridging factor, TRAM, to activate a MyD88-independent pathway that results in type I interferon expression. Interestingly, both Mal and TRAM are localised initially at the plasma membrane. In this Opinion, I suggest a possible mechanism by which endosomal acidification triggers the differential adaptor usage of TLR4. I discuss the evidence of the pH sensitivity of TLR4 and propose a new dimerisation mode for TLR4 based on the crystal structure of the related receptor TLR3 bound to its ligand, double-stranded RNA.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. (mg308@cam.ac.uk
authors.forename: Monique
authors.initials: M
authors.lastname: Gangloff
mesh_terms: D016207:Cytokines / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000378:metabolism* / Q000628:therapy; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4