UniProt functional annotation for O00206



	UniProt functional annotation for O00206

UniProt code: O00206.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195,PubMed:21393102). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465). {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:15809303, ECO:0000269|PubMed:16622205, ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187, ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:29038465, ECO:0000269|PubMed:9237759}.

Catalytic activity: Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204};

Subunit: Belongs to the lipopolysaccharide (LPS) receptor, a multi- protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP via their respective TIR domains (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity). Interacts with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (PubMed:21393102, PubMed:17098818). {ECO:0000250|UniProtKB:Q9QUK6, ECO:0000269|PubMed:11274165, ECO:0000269|PubMed:14519765, ECO:0000269|PubMed:15356101, ECO:0000269|PubMed:17098818, ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20865800, ECO:0000269|PubMed:21393102, ECO:0000269|PubMed:21602844, ECO:0000269|PubMed:25736436, ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:30573680}.

Subunit: (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC. {ECO:0000269|PubMed:23569230}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:11274165, ECO:0000269|PubMed:17098818, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:21393102, ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:9237759}; Single-pass type I membrane protein {ECO:0000269|PubMed:11274165}. Early endosome {ECO:0000269|PubMed:27022195}. Cell projection, ruffle {ECO:0000250|UniProtKB:Q9QUK6}. Note=Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation. {ECO:0000269|PubMed:20037584}.

Tissue specificity: Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:9237759, PubMed:27022195). {ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:9237759, ECO:0000269|PubMed:9435236}.

Domain: The TIR domain mediates interaction with NOX4. {ECO:0000269|PubMed:15356101}.

Domain: The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255|PROSITE-ProRule:PRU00204}.

Ptm: N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS- response. Likewise, mutants lacking two or more of the other N- glycosylation sites were deficient in interaction with LPS. {ECO:0000269|PubMed:11706042, ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:22363519}.

Ptm: Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide. {ECO:0000250|UniProtKB:Q9QUK6}.

Polymorphism: Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS. {ECO:0000269|PubMed:10835634}.

Miscellaneous: His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4- deficient mice expresses human TLR4 has been proposed. {ECO:0000305|PubMed:20711192}.

Similarity: Belongs to the Toll-like receptor family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195,PubMed:21393102). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465). {ECO:0000269\|PubMed:10835634, ECO:0000269\|PubMed:15809303, ECO:0000269\|PubMed:16622205, ECO:0000269\|PubMed:17478729, ECO:0000269\|PubMed:20037584, ECO:0000269\|PubMed:20711192, ECO:0000269\|PubMed:23880187, ECO:0000269\|PubMed:27022195, ECO:0000269\|PubMed:29038465, ECO:0000269\|PubMed:9237759}.


Catalytic activity:		Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204};
Subunit:		Belongs to the lipopolysaccharide (LPS) receptor, a multi- protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP via their respective TIR domains (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity). Interacts with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (PubMed:21393102, PubMed:17098818). {ECO:0000250\|UniProtKB:Q9QUK6, ECO:0000269\|PubMed:11274165, ECO:0000269\|PubMed:14519765, ECO:0000269\|PubMed:15356101, ECO:0000269\|PubMed:17098818, ECO:0000269\|PubMed:17803912, ECO:0000269\|PubMed:19252480, ECO:0000269\|PubMed:20037584, ECO:0000269\|PubMed:20865800, ECO:0000269\|PubMed:21393102, ECO:0000269\|PubMed:21602844, ECO:0000269\|PubMed:25736436, ECO:0000269\|PubMed:27022195, ECO:0000269\|PubMed:30573680}.
Subunit:		(Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC. {ECO:0000269\|PubMed:23569230}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:11274165, ECO:0000269\|PubMed:17098818, ECO:0000269\|PubMed:20037584, ECO:0000269\|PubMed:21393102, ECO:0000269\|PubMed:27022195, ECO:0000269\|PubMed:9237759}; Single-pass type I membrane protein {ECO:0000269\|PubMed:11274165}. Early endosome {ECO:0000269\|PubMed:27022195}. Cell projection, ruffle {ECO:0000250\|UniProtKB:Q9QUK6}. Note=Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation. {ECO:0000269\|PubMed:20037584}.
Tissue specificity:		Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:9237759, PubMed:27022195). {ECO:0000269\|PubMed:27022195, ECO:0000269\|PubMed:9237759, ECO:0000269\|PubMed:9435236}.
Domain:		The TIR domain mediates interaction with NOX4. {ECO:0000269\|PubMed:15356101}.
Domain:		The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255\|PROSITE-ProRule:PRU00204}.
Ptm:		N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS- response. Likewise, mutants lacking two or more of the other N- glycosylation sites were deficient in interaction with LPS. {ECO:0000269\|PubMed:11706042, ECO:0000269\|PubMed:17803912, ECO:0000269\|PubMed:19252480, ECO:0000269\|PubMed:22363519}.
Ptm:		Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide. {ECO:0000250\|UniProtKB:Q9QUK6}.
Polymorphism:		Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS. {ECO:0000269\|PubMed:10835634}.
Miscellaneous:		His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4- deficient mice expresses human TLR4 has been proposed. {ECO:0000305\|PubMed:20711192}.
Similarity:		Belongs to the Toll-like receptor family. {ECO:0000305}.