Trafficking and processing of endosomal TLR (Homo sapiens)

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2, 4, 5, 11, 23...285, 20305, 13, 24, 328, 10, 18, 19, 21...2, 4, 5, 9, 12...1, 7, 9, 14-17, 29C-ter TLR7 dimer FL-TLR9 dimer FL-TLR9 dimer intracellular TLR3/7/8/9 folded FL-TLR7/8/9 TLR3/7/8/9 C-ter-TLR9 dimer N-ter TLR9 dimer intracellular TLRUNC93B1 endolysosome lumenFL-TLR8 dimer Golgi lumenTLR8 dimer FL-TLR8 dimer neutral pHATP-bound Gp96 dimerCNPY3TLR7/8/9 Apo-GP96 dimer FL-TLR9FL-TLR9 endolysosome lumenFL-TLR7 dimer intracellular TLRUNC93B1 endoplasmic reticulum lumencytosolFL-TLR7 dimer FL-TLR7 dimer TLR8 ADPCNPY3TLR7 TLR8 dimerTLR9 TLR8 CTSSUNC93B1 UNC93B1TLR3 FL-TLR7 dimerCNPY3 TLR3 TLR7UNC93B1 HSP90B1 TLR7 TLR3C-ter TLR7 dimerintracellular TLRUNC93B1TLR3TLR9 folded FL-TLR7/8/9TLR9Legumain/CathepsinsN-ter TLR9 dimerTLR7/8/9TLR8 Apo-GP96 dimerintracellular TLRUNC93B1UNC93B1TLR9intracellular TLR3/7/8/9C-ter-TLR9 dimerATPTLR9 ATP ATP-bound Gp96 dimerCNPY3TLR7/8/9HSP90B1 TLR7 FL-TLR9 dimerH+303, 63, 6


Description

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.<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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1679131</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114912view16:42, 25 January 2021ReactomeTeamReactome version 75
113357view11:43, 2 November 2020ReactomeTeamReactome version 74
112566view15:53, 9 October 2020ReactomeTeamReactome version 73
101479view11:34, 1 November 2018ReactomeTeamreactome version 66
101017view21:14, 31 October 2018ReactomeTeamreactome version 65
100553view19:48, 31 October 2018ReactomeTeamreactome version 64
100101view16:33, 31 October 2018ReactomeTeamreactome version 63
99651view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99253view12:45, 31 October 2018ReactomeTeamreactome version 62
93870view13:42, 16 August 2017ReactomeTeamreactome version 61
93437view11:23, 9 August 2017ReactomeTeamreactome version 61
88364view16:42, 1 August 2016FehrhartOntology Term : 'pathway pertinent to protein folding, sorting, modification, translocation and degradation' added !
86528view09:20, 11 July 2016ReactomeTeamreactome version 56
83309view10:45, 18 November 2015ReactomeTeamVersion54
81448view12:58, 21 August 2015ReactomeTeamVersion53
76922view08:19, 17 July 2014ReactomeTeamFixed remaining interactions
76627view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75958view10:01, 11 June 2014ReactomeTeamRe-fixing comment source
75660view10:56, 10 June 2014ReactomeTeamReactome 48 Update
75015view13:52, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74659view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATP-bound Gp96 dimer

CNPY3

TLR7/8/9		ComplexREACT_119946 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Apo-GP96 dimerComplexREACT_119705 (Reactome)
C-ter TLR7 dimerComplexREACT_120221 (Reactome)
C-ter-TLR9 dimerComplexREACT_119600 (Reactome)
CNPY3 ProteinQ9BT09 (Uniprot-TrEMBL)
CNPY3ProteinQ9BT09 (Uniprot-TrEMBL)
CTSSProteinP25774 (Uniprot-TrEMBL)
FL-TLR7 dimerComplexREACT_119775 (Reactome)
FL-TLR9 dimerComplexREACT_120181 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
HSP90B1 ProteinP14625 (Uniprot-TrEMBL)
Legumain/CathepsinsProteinREACT_119541 (Reactome)
N-ter TLR9 dimerComplexREACT_119555 (Reactome)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TLR7 ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR7/8/9ProteinREACT_119993 (Reactome)
TLR7ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR8 ProteinQ9NR97 (Uniprot-TrEMBL)
TLR8 dimerComplexREACT_119029 (Reactome)
TLR9 ProteinQ9NR96 (Uniprot-TrEMBL)
TLR9ProteinQ9NR96 (Uniprot-TrEMBL)
UNC93B1 ProteinQ9H1C4 (Uniprot-TrEMBL)
UNC93B1ProteinQ9H1C4 (Uniprot-TrEMBL)
folded FL-TLR7/8/9ComplexREACT_119319 (Reactome)
intracellular TLR UNC93B1ComplexREACT_119414 (Reactome)
intracellular TLR UNC93B1ComplexREACT_119522 (Reactome)
intracellular TLR3/7/8/9ComplexREACT_120129 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowREACT_118678 (Reactome)
ATPREACT_118729 (Reactome)
Apo-GP96 dimerArrowREACT_118678 (Reactome)
Apo-GP96 dimerREACT_118729 (Reactome)
C-ter TLR7 dimerArrowREACT_118824 (Reactome)
C-ter-TLR9 dimerArrowREACT_118824 (Reactome)
CNPY3ArrowREACT_118678 (Reactome)
CNPY3REACT_118729 (Reactome)
CTSSREACT_118693 (Reactome)
FL-TLR7 dimerArrowREACT_118774 (Reactome)
FL-TLR7 dimerREACT_118824 (Reactome)
FL-TLR9 dimerArrowREACT_118774 (Reactome)
FL-TLR9 dimerREACT_118824 (Reactome)
Legumain/CathepsinsREACT_118824 (Reactome)
REACT_118678 (Reactome) Folded TLR9 dissociates from GP96:CNPY3 complex (Liu B et al 2010) and translocates to the endolysosome with the aid of the membrane protein UNC93b. Here we assume that TLR7 and TLR8 behave in a similar manner.
REACT_118693 (Reactome) TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011).
REACT_118729 (Reactome) GP96 (also known as GRP94, HSP90b1), a paralogue of HSP90 in the endoplasmic reticulum, acts as a chaperone for some integrines and Toll-like receptors. Macrophages or B-cells from gp96 knockout mice have abrogated function of TLR2, 4, 5, 7 and 9, but not TLR3 (Yang Y et al 2007, Liu B and Li Z 2008, Staron M et al 2010). GP96 interacts with TLRs and integrines via its C-terminal hydrophobic domain, formed by residues 652-678 (Wu S et al 2012). GP96 functions as a V-shaped dimer in ATP-dependent manner, however it remains unclear how ATP hydrolysis-dependent conformational changes of GP96 are regulated (Li Z and Srivastava PK 1993).

GP96 forms a complex with co-chaperone CNPY3, also known as PRAT4A. GP96-CNPY3 promotes the proper post-translational ectodomain folding of TLRs, but not TLR3 (Liu B et al 2010).

REACT_118774 (Reactome) TLR3, 7, 8 and 9 activation occurs within acidified endolysosomal compartments. Inhibition of endosome acidification with bafilomicin A or chloroquine abrogated TLR's-mediated responses to pathogen-derived nucleic acids (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006, Kuznik A et al 2011). Upon stimulation, TLR3, 7, and 9 (and possibly TLR8) are transported to the signaling endosomes by UNC93B1, whereby they become functional receptors and bind to their specific ligands (Kim et al 2008, Ewald et al 2011). Although UNC93B1 is critically involved in TLRs trafficking it was dispensable for ligand binding by these TLRs (Kim YM et al 2008).
REACT_118791 (Reactome) TLRs traffic through the Golgi complex by the conventional secretory pathway and are routed to endolysosomes where they bind their ligands (Chockalingam A et al 2008, Ewald SE et al 2011). .
REACT_118802 (Reactome) 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.

REACT_118824 (Reactome) Endosome maturation (acidification) is required for both the activation of TLR9 and TLR7 through proteolytic cleavage and the disassembly of pathogens, thereby releasing the TLR ligands within them. TLR7 and TLR9 are cleaved within their ectodomains by pH-sensitive cysteine endopeptidases. Cathepsins (CTS) B, K, L, and S, and asparagine endopeptidase (AEP, also known as legumain) have been implicated in endolysosomal TLR processing, however, several groups have reported somewhat controversial results on the role of specific proteases (Matsumoto F et al 2008, Park B et al 2008, Ewald SE et al 2008, Ewald SE et al 2011, Sepulveda FE et al 2009).

One study showed that TLR9 proteolysis is a multistep process with the initial cleavage that can be mediated by AEP or multiple members of the cathepsin family. The second event is mediated exclusively by cathepsins. TLR7 and TLR3 were reported to be cleaved in a similar manner (Ewald SE et al 2011). Cleavage of TLR3 is not shown in this reaction, since other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, suggesting that TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).

Both full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only the processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008).

TLR3ArrowREACT_118774 (Reactome)
TLR7/8/9REACT_118729 (Reactome)
TLR8 dimerArrowREACT_118774 (Reactome)
UNC93B1ArrowREACT_118774 (Reactome)
UNC93B1REACT_118802 (Reactome)
folded FL-TLR7/8/9ArrowREACT_118678 (Reactome)
intracellular TLR3/7/8/9REACT_118802 (Reactome)

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