UniProt functional annotation for Q2EEY0



	UniProt functional annotation for Q2EEY0

UniProt code: Q2EEY0.

Organism: Equus caballus (Horse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.

Function: Key component of innate and adaptive immunity. TLRs (Toll- like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine- phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (By similarity). {ECO:0000250|UniProtKB:Q9NR96, ECO:0000269|PubMed:25686612}.

Subunit: Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (PubMed:25686612). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (By similarity). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses. Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum. Interacts with SMPDL3B (By similarity). {ECO:0000250|UniProtKB:Q9EQU3, ECO:0000250|UniProtKB:Q9NR96, ECO:0000269|PubMed:25686612}.

Subcellular location: Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9EQU3}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:Q9EQU3}. Endosome {ECO:0000250|UniProtKB:Q9EQU3}. Lysosome {ECO:0000250|UniProtKB:Q9EQU3}. Cytoplasmic vesicle {ECO:0000250|UniProtKB:Q9EQU3}. Cytoplasmic vesicle, phagosome {ECO:0000250|UniProtKB:Q9EQU3}. Cell membrane {ECO:0000269|PubMed:19548205}. Cytoplasm {ECO:0000269|PubMed:19548205}. Nucleus {ECO:0000269|PubMed:19548205}. Note=Relocalizes from endoplasmic reticulum to endosome and lysosome upon stimulation with agonist. Exit from the ER requires UNC93B1. Endolysosomal localization is required for proteolytic cleavage and subsequent activation. Intracellular localization of the active receptor may prevent from responding to self nucleic acid. {ECO:0000250|UniProtKB:Q9EQU3}.

Tissue specificity: Expressed in airway epithelium, vascular endothelium and inflammatory cells in blood vessels of the lungs (at protein level). Highly expressed in pulmonary intravascular macrophages (PIMs) and to a lesser extent in alveolar macrophages, neutrophiles, type-II alveolar epithelial cells and bronchial epithelial cells of the lungs (at protein level) (PubMed:19548205). High constitutive intracellular expression in leukocytes including polymorphonuclear leukocytes (PMNs), CD4 and CD8 T cells (at protein level) (PubMed:18462806). Expressed throughout the respiratory tract including larynx, upper, middle and lower trachea, and bronchus in isolated equine respiratory epithelial cells (ERECs) and in fully differentiated ERECs cultured at the air-fluid interface (AFI) (at protein level) (PubMed:21292331). Constitutively expressed in peripheral blood mononuclear cells (PBMCs), lymph nodes and spleen. The level of expression in PBMCs is about 2- to 3-fold higher than that in lymph nodes and spleen. Very low expression in liver, heart, lung, kidney, small intestine, colon and stomach (PubMed:18462806). Low expression in the airway tissue epithelium of the larynx, upper trachea, middle tranchea, lower trachea, bronchus and spleen, and more abundant expression in mesenteric lymph node. Not expressed in fully differentiated bronchus epithelial cells cultured at the AFI for four weeks (PubMed:21292331). Expressed in gingival tissue (PubMed:27270960). {ECO:0000269|PubMed:18462806, ECO:0000269|PubMed:19548205, ECO:0000269|PubMed:21292331, ECO:0000269|PubMed:27270960}.

Developmental stage: Expression increases with age in neutrophils of an individual foal aged between 2 to 56 days (PubMed:22197007). Expression in neutrophils of a foal at age 1 day, another different foal at age 56 days, and of an adult horse is constitutive at a very low level (PubMed:19819162). {ECO:0000269|PubMed:19819162, ECO:0000269|PubMed:22197007}.

Induction: By mitogen phytohaemagglutinin (PHA) in peripheral blood mononuclear cells (PBMCs) (PubMed:18462806). By lipopolysaccharide (LPS) in cells of the lung septa. This induction is abolished by gadolinium chloride treatment which depletes pulmonary intravascular macrophages (PIMs) (PubMed:19548205). By synthetic class C cytidine- phosphate-guanosine oligodeoxynucleotides (CpG-ODNs) in PBMCs (PubMed:25066759). Synthetic class B CpG-ODN does not induce a significant increase of expression in vitro in neutrophils of foals aged between 2 to 56 days nor in adult horses (PubMed:22197007, PubMed:19819162). Expression level in neutrophils is not significantly changed by virulent strain of R.equi bacterium (PubMed:19819162). Up- regulated by neuropathogenic equine herpesvirus-1 (EHV-1) infection in fully differentiated equine respiratory epithelial cells (ERECs) cultured at the air-fluid interface (AFI) (PubMed:24560592). Up- regulated in gingival tissue in individuals with equine periodontal disease. 16-fold increase in expression at diseased sites of the gums compared to healthy sites of the same animal (PubMed:27270960). {ECO:0000269|PubMed:18462806, ECO:0000269|PubMed:19548205, ECO:0000269|PubMed:19819162, ECO:0000269|PubMed:22197007, ECO:0000269|PubMed:24560592, ECO:0000269|PubMed:25066759, ECO:0000269|PubMed:27270960}.

Ptm: Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. {ECO:0000250|UniProtKB:Q9EQU3}.

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

Annotations taken from UniProtKB at the EBI.


Organism:		Equus caballus (Horse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.



Function:		Key component of innate and adaptive immunity. TLRs (Toll- like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine- phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (By similarity). {ECO:0000250\|UniProtKB:Q9NR96, ECO:0000269\|PubMed:25686612}.


Subunit:		Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (PubMed:25686612). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (By similarity). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses. Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum. Interacts with SMPDL3B (By similarity). {ECO:0000250\|UniProtKB:Q9EQU3, ECO:0000250\|UniProtKB:Q9NR96, ECO:0000269\|PubMed:25686612}.
Subcellular location:		Endoplasmic reticulum membrane {ECO:0000250\|UniProtKB:Q9EQU3}; Single-pass type I membrane protein {ECO:0000250\|UniProtKB:Q9EQU3}. Endosome {ECO:0000250\|UniProtKB:Q9EQU3}. Lysosome {ECO:0000250\|UniProtKB:Q9EQU3}. Cytoplasmic vesicle {ECO:0000250\|UniProtKB:Q9EQU3}. Cytoplasmic vesicle, phagosome {ECO:0000250\|UniProtKB:Q9EQU3}. Cell membrane {ECO:0000269\|PubMed:19548205}. Cytoplasm {ECO:0000269\|PubMed:19548205}. Nucleus {ECO:0000269\|PubMed:19548205}. Note=Relocalizes from endoplasmic reticulum to endosome and lysosome upon stimulation with agonist. Exit from the ER requires UNC93B1. Endolysosomal localization is required for proteolytic cleavage and subsequent activation. Intracellular localization of the active receptor may prevent from responding to self nucleic acid. {ECO:0000250\|UniProtKB:Q9EQU3}.
Tissue specificity:		Expressed in airway epithelium, vascular endothelium and inflammatory cells in blood vessels of the lungs (at protein level). Highly expressed in pulmonary intravascular macrophages (PIMs) and to a lesser extent in alveolar macrophages, neutrophiles, type-II alveolar epithelial cells and bronchial epithelial cells of the lungs (at protein level) (PubMed:19548205). High constitutive intracellular expression in leukocytes including polymorphonuclear leukocytes (PMNs), CD4 and CD8 T cells (at protein level) (PubMed:18462806). Expressed throughout the respiratory tract including larynx, upper, middle and lower trachea, and bronchus in isolated equine respiratory epithelial cells (ERECs) and in fully differentiated ERECs cultured at the air-fluid interface (AFI) (at protein level) (PubMed:21292331). Constitutively expressed in peripheral blood mononuclear cells (PBMCs), lymph nodes and spleen. The level of expression in PBMCs is about 2- to 3-fold higher than that in lymph nodes and spleen. Very low expression in liver, heart, lung, kidney, small intestine, colon and stomach (PubMed:18462806). Low expression in the airway tissue epithelium of the larynx, upper trachea, middle tranchea, lower trachea, bronchus and spleen, and more abundant expression in mesenteric lymph node. Not expressed in fully differentiated bronchus epithelial cells cultured at the AFI for four weeks (PubMed:21292331). Expressed in gingival tissue (PubMed:27270960). {ECO:0000269\|PubMed:18462806, ECO:0000269\|PubMed:19548205, ECO:0000269\|PubMed:21292331, ECO:0000269\|PubMed:27270960}.
Developmental stage:		Expression increases with age in neutrophils of an individual foal aged between 2 to 56 days (PubMed:22197007). Expression in neutrophils of a foal at age 1 day, another different foal at age 56 days, and of an adult horse is constitutive at a very low level (PubMed:19819162). {ECO:0000269\|PubMed:19819162, ECO:0000269\|PubMed:22197007}.
Induction:		By mitogen phytohaemagglutinin (PHA) in peripheral blood mononuclear cells (PBMCs) (PubMed:18462806). By lipopolysaccharide (LPS) in cells of the lung septa. This induction is abolished by gadolinium chloride treatment which depletes pulmonary intravascular macrophages (PIMs) (PubMed:19548205). By synthetic class C cytidine- phosphate-guanosine oligodeoxynucleotides (CpG-ODNs) in PBMCs (PubMed:25066759). Synthetic class B CpG-ODN does not induce a significant increase of expression in vitro in neutrophils of foals aged between 2 to 56 days nor in adult horses (PubMed:22197007, PubMed:19819162). Expression level in neutrophils is not significantly changed by virulent strain of R.equi bacterium (PubMed:19819162). Up- regulated by neuropathogenic equine herpesvirus-1 (EHV-1) infection in fully differentiated equine respiratory epithelial cells (ERECs) cultured at the air-fluid interface (AFI) (PubMed:24560592). Up- regulated in gingival tissue in individuals with equine periodontal disease. 16-fold increase in expression at diseased sites of the gums compared to healthy sites of the same animal (PubMed:27270960). {ECO:0000269\|PubMed:18462806, ECO:0000269\|PubMed:19548205, ECO:0000269\|PubMed:19819162, ECO:0000269\|PubMed:22197007, ECO:0000269\|PubMed:24560592, ECO:0000269\|PubMed:25066759, ECO:0000269\|PubMed:27270960}.
Ptm:		Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. {ECO:0000250\|UniProtKB:Q9EQU3}.
Similarity:		Belongs to the Toll-like receptor family. {ECO:0000305}.