Different dimerisation mode for TLR4 upon endosomal acidification?

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.