Release from UNC93B1 reinforces the compartmentalized activation of select TLRs

• Published in: Nature (London) Vol. 575; no. 7782; pp. 371 - 374
• Main Authors: Majer, Olivia, Liu, Bo, Woo, Brian J., Kreuk, Lieselotte S. M., Van Dis, Erik, Barton, Gregory M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2019; Nature Publishing Group
• Subjects: 13; 13/106; 631/250/262/2106/2108; 631/250/38; 64/60; 82/1; 82/80; 96/31; 96/63; 96/95; Activation; Amino acids; Animals; Cell Line; Control; Deoxyribonucleic acid; DNA; Endosomes; Genomes; Humanities and Social Sciences; Humans; Influence; Intracellular; Ligands; Localization; Lupus; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane proteins; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Methods; Mice; Mice, Inbred C57BL; Microorganisms; Molecular modelling; multidisciplinary; Mutation; Nucleic acids; Protein Binding; Protein Transport; Radioactivation analysis; Receptors; Recognition; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Signal Transduction; TLR3 protein; TLR7 protein; TLR9 protein; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; Toll-like receptors; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1611-7

Nucleic acid-sensing Toll-like receptors (TLRs) are subject to complex regulation to facilitate the recognition of microbial DNA and RNA while limiting the recognition of an organism’s own nucleic acids 1 . Failure to properly regulate these TLRs can lead to autoimmune and autoinflammatory diseases 2 – 6 . Intracellular localization of these receptors is thought to be crucial for the discrimination between self and non-self 7 , but the molecular mechanisms that reinforce compartmentalized activation of intracellular TLRs remain poorly understood. Here we describe a mechanism that prevents the activation of TLR9 from locations other than endosomes. This control is achieved through the regulated release of the receptor from its trafficking chaperone UNC93B1, which occurs only within endosomes and is required for ligand binding and signal transduction. Preventing release of TLR9 from UNC93B1, either by mutations in UNC93B1 that increase affinity for TLR9 or through an artificial tether that impairs release, results in defective signalling. Whereas TLR9 and TLR3 are released from UNC93B1, TLR7 does not dissociate from UNC93B1 in endosomes and is regulated by distinct mechanisms. This work defines a checkpoint that reinforces the compartmentalized activation of TLR9, and provides a mechanism by which activation of individual endosomal TLRs may be distinctly regulated. The Toll-like receptor TLR9 is activated only after regulated release from its trafficking chaperone UNC93B1, which occurs within endosomes and is required for ligand binding and signal transduction.