intracellular TLR:UNC93B1 intracellular TLR3/7/8/9 Full-length TLR3/7/8/9 binds to UNC93B1 Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Mammalian UNC93B1, a multi-transmembrane protein, directly associates with transmembrane domains of TLR3, TLR7, TLR8 and TLR9 (and mouse TLR13) in the ER and facilitates their translocation to endolysosome compartments (Brinkmann et al 2007; Kim et al 2008; Itoh H et al 2011). Mutant mouse and human cells that lack functional UNC93B1 showed disrupted signaling via the endosomal TLRs (Taneda K et al 2006; Fukui et al 2009; Kim YM et al 2008; Qi R et al 2010; Koehn J et al 2007). Furthermore, defects in the human gene encoding UNC93B1 are associated with the increased susceptibility to herpes simplex encephalitis (HSE) in children (Casrouge A et al 2006).<p>TLR7 and TLR9 compete for UNC931-dependent trafficking and under normal circumstances TLR9 predominates over TLR7. This preference for TLR9 is mediated by an N-terminal domain in UNC93B1 and is reversed to TLR7 if UNC93B1 loses the preferential N-terminal binding site via mutation of aspartate at position 34. Loss of binding to TLR9 and preferential association with TLR7 resulted in hyperresponsiveness to RNA ligands (Fukui et al 2009).<p>TLR3 appears to translocate to the endosomal compartment with equal efficiency regardless of the presence or absence of the N-terminal domain that mediates preference for TLR9. Thus, endosomal TLR trafficking is orchestrated by UNC93B1 which determines how efficiently each TLR is able to move from the ER to the endolysosomes to initiate host responses. Pubmed16415873 Pubmed16973841 Pubmed17452530 Pubmed18082565 Pubmed18305481 Pubmed19451267 Pubmed20855885 Pubmed22164301 Reactome Database ID Release 431678921 Reactome, http://www.reactome.org ReactomeREACT_118802 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28