PathwayStep6675 PathwayStep6674 PathwayStep6673 PathwayStep6672 PathwayStep6671 PathwayStep6670 PathwayStep6669 TLR9 processing at neutral pH Endosomal TLRs pass through the Golgi Full-length TLR3/7/8/9 binds to UNC93B1 TLR processing at low pH UNC93B1 delivers endosomal full-length TLRs to endolysosome Folded full-length TLR7/8/9 dissociates from the GP96:CNPY3 complex TLR folding by chaperones GP96 and CNPY3 Trafficking and processing of endosomal TLR Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 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.<p>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.<p> 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).<p> 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). Pubmed15226270 Pubmed16144834 Pubmed16341217 Pubmed16857668 Pubmed18420935 Pubmed18776324 Pubmed18820679 Pubmed19521997 Pubmed21402738 Pubmed9799232 Reactome Database ID Release 431679131 Reactome, http://www.reactome.org ReactomeREACT_118632 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28