Key Points
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Toll-like receptors (TLRs) are type I transmembrane proteins that are involved in innate and adaptive immune responses to pathogens and are found on the surface of cells and in endosomal compartments. Humans have ten functional TLRs, whereas mice express twelve.
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The activation and function of both surface and endosomal TLRs depend on TLR accessory proteins. TLR accessory proteins can be involved in ligand delivery or recognition, or can function as endoplasmic reticulum (ER) chaperones or as trafficking or processing factors.
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LPS-binding protein, MD2, CD36 and CD14 all participate in ligand recognition for surface TLRs. Progranulin, CD14, HMGB1 and LL37 aid in ligand delivery and recognition for endosomal TLRs.
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The ER chaperones GRP94 and PRAT4A work together to allow for proper TLR folding and assembly. Delivery of endosomal TLRs from the ER to endolysosomes involves the scaffolding and trafficking factor UNC93B1; adaptor protein 3 is required for the translocation of TLR9 to lysosomes or lysosome-related organelles in bone marrow-derived macrophages.
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Cathepsins and asparagine endopeptidase are proteases required for the cleavage and activation of endosomal TLRs.
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The study of TLR cofactor function has contributed to a better understanding of TLR signalling pathways and innate and adaptive immunity.
Abstract
Toll-like receptors (TLRs) are essential components of the innate immune system. Accessory proteins are required for the biosynthesis and activation of TLRs. Here, we summarize recent findings on TLR accessory proteins that are required for cell-surface and endosomal TLR function, and we classify these proteins based on their function as ligand-recognition and delivery cofactors, chaperones and trafficking proteins. Because of their essential roles in TLR function, targeting of such accessory proteins may benefit strategies aimed at manipulating TLR activation for therapeutic applications.
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We thank M. M. Brinkmann and Y.-M. Kim for critical reading of the manuscript.
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Glossary
- Alarmins
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Endogenous mediators that are released by necrotic cells in response to infection or injury and that interact with pattern-recognition receptors to activate innate immune cells.
- Acute-phase protein
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A member of a group of proteins — including C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein — that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.
- Lipid rafts
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Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein organization.
- Sterile inflammation
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An inflammatory response triggered by tissue damage in the absence of infection.
- Amphipathic peptide
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A peptide that contains hydrophilic and hydrophobic domains, which allow the peptide to interact both with charged residues and with lipophilic structures.
- Endosomes
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Vesicles of the endocytic pathway that transport proteins from the plasma membrane and the Golgi compartment and have a mildly acidic pH.
- Paralogue
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A homologous gene that resulted from a gene duplication event.
- Small hairpin RNA
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One of the two most common forms of short (usually 21-base-pairs long) double-stranded RNAs used for gene silencing. The other form is known as small interfering RNA (siRNA).
- Lysosomes
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Organelles involved in protein degradation that have a low pH and correspond to the last step of the endocytic pathway.
- Lysosome-related organelles
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(LROs). Cell type-specific compartments that share properties with lysosomes but have specialized functions. LROs include melanosomes, lytic granules, MHC class II compartments, platelet-dense granules, basophil granules and azurophil granules.
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Lee, C., Avalos, A. & Ploegh, H. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 12, 168–179 (2012). https://doi.org/10.1038/nri3151
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DOI: https://doi.org/10.1038/nri3151
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