Reactome | Full-length TLR3/7/8/9 binds to UNC93B1

Full-length TLR3/7/8/9 binds to UNC93B1

Stable Identifier

R-HSA-1678921

Type

Reaction [binding]

Species

Homo sapiens

Compartment

endoplasmic reticulum membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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).

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).

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.

Literature References

PubMed ID	Title	Journal	Year
20855885	Secretion of the human Toll-like receptor 3 ectodomain is affected by single nucleotide polymorphisms and regulated by Unc93b1 San Mateo, L, Mills, J, Schreiter, J, Jordan, JL, Lamb, R, Ranjith-Kumar, CT, Qi, R, Kao, CC, Hoose, S, Sawant, KV	J Biol Chem	2010
16973841	Herpes simplex virus encephalitis in human UNC-93B deficiency Beutler, B, Abel, L, Alcais, A, Dulac, O, Lebon, P, Lorenzo, L, Plancoulaine, S, Du, X, Nicolas, N, Rozenberg, F, Sénéchal, B, Miller, RL, Tabeta, K, Geissmann, F, Casrouge, A, Héron, B, Yang, K, Jouanguy, E, de Villemeur, TB, Puel, A, Picard, C, Eidenschenk, C, Mignot, C, Zhang, SY, Hoebe, K, Mahfoufi, N, Casanova, JL, Tardieu, M	Science	2006
19451267	Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing Beutler, B, Matsumoto, F, Miyake, K, Tabeta, K, Saitoh, S, Fukui, R, Kozuka-Hata, H, Oyama, M	J Exp Med	2009
16415873	The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9 Beutler, B, Sovath, S, Cooke, M, Herskovits, AA, Tabeta, K, Goode, J, Wiltshire, T, Shamel, L, Mann, N, Mudd, S, Portnoy, DA, Du, X, Steinberg, BE, Tarantino, LM, Janssen, EM, Georgel, P, Crozat, K, Hoebe, K, Grinstein, S	Nat Immunol	2006
17452530	The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling Beutler, B, Ploegh, HL, Spooner, E, Kim, YM, Hoebe, K, Brinkmann, MM	J Cell Biol	2007
18305481	UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes Ploegh, HL, Kim, YM, Paquet, ME, Brinkmann, MM	Nature	2008
22164301	UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling Matsumoto, M, Iwano, K, Watanabe, A, Funami, K, Itoh, H, Tatematsu, M, Seya, T	PLoS ONE	2011
18082565	Assessing the function of human UNC-93B in Toll-like receptor signaling and major histocompatibility complex II response Beutler, B, Koehn, J, Dwertmann, A, Rot, A, Korthäuer, U, Jaritz, M, Zurini, M, Huesken, D	Hum Immunol	2007