Trafficking and processing of endosomal TLR

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Homo sapiens
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Mammalian TLR3, TLR7, TLR8, TLR9 are endosomal receptors that sense nucleic acids that have been released from endocytosed/phagocytosed bacteria, viruses or parasites. These TLRs have a ligand-recognition domain that faces the lumen of the endosome (which is topologically equivalent to the outside of the cell), a transmembrane domain, and a signaling domain that faces the cytosol.

Under normal conditions, self nucleic acids are not recognized by TLRs due to multiple levels of regulation including receptor compartmentalization, trafficking and proteolytic processing (Barton GM et al 2006, Ewald SE et al 2008). At steady state TLR3, TLR7, TLR8, TLR9 reside primarily in the endoplasmic reticulum (ER), however, their activation by specific ligands only occurs within acidified endolysosomal compartments (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006). Several chaperon proteins associate with TLRs in the ER to provide efficient translocation to endolysosome. Upon reaching endolysosomal compartments the ectodomains of TLR7 and TLR9 are proteolytically cleaved by cysteine endoproteases. Both full-length and cleaved C-terminus of TLR9 bind CpG-oligodeoxynucleotides, however it has been proposed that only the processed receptor is functional.

Although similar cleavage of TLR3 has been reported by Ewald et al 2011, other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, thus TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).

There are no data on TLR8 processing, although the cell biology of TLR8 is probably similar to TLR9 and TLR7 (Gibbard RJ et al 2006, Wei T et al 2009).

Literature References
PubMed ID Title Journal Year
16341217 Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA

Barton, GM, Kagan, JC, Medzhitov, R

Nat Immunol 2006
16857668 Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling

Morley, PJ, Gibbard, RJ, Gay, NJ

J Biol Chem 2006
19521997 Homology modeling of human Toll-like receptors TLR7, 8, and 9 ligand-binding domains

Stark, RW, Jamitzky, F, Gong, J, Heckl, WM, Rössle, SC, Wei, T

Protein Sci 2009
9799232 CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation

Miethke, T, Sparwasser, T, Hacker, H, Heeg, K, Schmid, R, Lipford, GB, Liptay, S, Wagner, H, Mischak, H

EMBO J 1998
16144834 Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH

de Bouteiller, O, Caux, C, Hubac, S, Merck, E, Trinchieri, G, Benguigui, B, Bates, EE, Hasan, UA

J Biol Chem 2005
18820679 The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Barton, GM, Wickliffe, KE, Ewald, SE, Chapman, HA, Lau, L, Lee, BL, Shi, GP

Nature 2008
15226270 The cytoplasmic 'linker region' in Toll-like receptor 3 controls receptor localization and signaling

Matsumoto, M, Oshiumi, H, Funami, K, Akazawa, T, Seya, T, Yamamoto, A

Int Immunol 2004
18776324 Significance of the N-terminal histidine-rich region for the function of the human toll-like receptor 3 ectodomain

Matsumoto, M, Tsujita, T, Nishikawa, S, Tokisue, T, Hasegawa, T, Seya, T, Fukuda, K, Watanabe, T

Nucleic Acids Symp Ser (Oxf) 2008
18420935 Structural basis of toll-like receptor 3 signaling with double-stranded RNA

Davies, DR, Leonard, JN, Shiloach, J, Botos, I, Liu, L, Wang, Y, Segal, DM

Science 2008
21402738 Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase

Barton, GM, Lee, J, Ewald, SE, Wang, M, Bogyo, M, Engel, A

J Exp Med 2011
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