The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor
By Sarah E. Ewald, Bettina L. Lee, Laura Lau, Katherine E. Wickliffe, G. Shi, H. Chapman, G. Barton. Nature, 2008
638 citations recorded by the source corpus.
Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.
View Paper: https://www.semanticscholar.org/paper/0b27e3503a3d5e45279f74f40f906334e622acf1
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- G. Barton
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Citations in the corpus
- Endosome maturation (2011, background): “For example, TLR9 requires cathepsin-mediated cleavage of its ectodomain to initiate signalling (Ewald et al, 2008).”
- Mechanism of Endosomal TLR Inhibition by Antimalarial Drugs and Imidazoquinolines (2011, background): “The role of proteolysis and endosomal acidification connected to it has been reported for TLR9 activation (24, 25).”
- Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, unknown): “However, these TLRs are synthesized in an inactive state and must be proteolytically cleaved to become active (172, 173).”
- A cell biological view of Toll-like receptor function: regulation through compartmentalization (2009, background): “Biochemical analyses of TLR9 in macrophages and DCs led to the discovery of a processed form of the receptor that is exclusively present in endolysosome”
- Pattern recognition receptors and inflammation. (2010, background): “When TLR9 is recruited from the ER to the endolysosome, it undergoes processing by proteases, such as cathepsins, in the endolysosome (Ewald et al., 2008; Park et al., 2008).”