Recent work examining the cell biology of Toll-like receptors (TLRs) illustrates how basic aspects of the cellular machinery contribute to receptor function and regulation.
Despite residing on several organelles, all TLRs are first transported to the Golgi complex before being routed to the appropriate location. Bacterium-sensing TLRs probably follow the default secretory pathway from the Golgi to the cell surface, whereas TLRs that detect viral nucleic acids are delivered to endolysosomes by the chaperone Unc93B1.
Compartment-specific activity of nucleic acid-sensing TLRs (for example, TLR7 and TLR9) is maintained by compartment-specific cleavage events that generate functional receptors. These cleavage events are probably mediated by lysosomal cathepsins, and consequently nucleic acid-sensing TLRs are only active in endolysosomes.
Bacterium-sensing TLRs (such as TLR2 and TLR4) use sorting adaptor proteins to determine the subcellular sites of signal transduction. For TLR4, the sorting adaptors TIRAP (TIR domain-containing adaptor protein) and TRAM (TRIF-related adaptor molecule) function to recruit their downstream signalling machinery to the plasma membrane and endosomes, respectively.
Sorting adaptor proteins are positioned in specific intracellular subcompartments by interacting with phosphoinositides. Regulators of phosphoinositide metabolism may therefore control the activity of specific TLR signalling pathways.
Endolysosomes seem to be the sole subcompartments that allow a TLR-dependent interferon response. Consequently, the plasma membrane-localized TLR4 must first be internalized into endosomes before the interferon-inducing signalling pathway can be activated.
An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand–receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.
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The authors thank members of their laboratories for helpful discussions and the National Institutes of Health, USA (AI072429 to G.M.B., AI072955 to J.C.K.) and the Lupus Research Institute (G.M.B.) for funding support.
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Barton, G., Kagan, J. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9, 535–542 (2009). https://doi.org/10.1038/nri2587
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