UniProt functional annotation for P9WK61



	UniProt functional annotation for P9WK61

UniProt code: P9WK61.

Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).

Taxonomy: Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.

Function: Based on its structure might be involved in ligand transport (Ref.25) (By similarity). {ECO:0000250|UniProtKB:P65307, ECO:0000305|Ref.25}.

Function: A host TLR2 agonist (PubMed:10426995, PubMed:11441098, PubMed:12874328). Plays a complicated role in bacterial interactions with the host immune system; some effects favor the host (induces interleukin 1-beta and IL-12 p40 (IL12B), both increase the host's immune response) while others favor the bacteria (increases growth in monocyte-derived macrophages and decreases host MHC class II (MHC-II) expression and antigen processing) (PubMed:16177361). Induces host (human and mouse) IL-12 p40 (IL12B, a proinflammatory cytokine) release by monocyte cell lines via TLR2 and CD14 (PubMed:10426995). Induces host (human) monocytes to produce TNF-alpha, IL-6 and IL-12 p40; LpqH is a more potent inducer than PstS1 (PubMed:16622205). Inhibits MHC-II expression and antigen processing in host (mouse) macrophages via TLR2 (independently of TLR4) probably via the lipid modification (PubMed:11441098). Stimulates host (human) dendritic cell maturation to become MHC-II-positive antigen presenting cells via TLR2, which depends on lipidation; nonlipidated protein does not stimulate maturation (PubMed:11160304). Inhibits host (human and mouse) IFN-gamma signaling in macrophages via TLR2; decreases IFN-gamma stimulated MHC-II antigen processing as well as decreasing IFN-gamma-mediated up-regulation of immunoglobulin gamma Fc receptor (FCGR1A), enabling the bacteria to evade the immune system (PubMed:12874328). In resting human CD4+ T- cells lipidated (but probably not nonlipidated protein) is a costimulatory ligand (with anti-CD3 and anti-CD28) for T-cell proliferation and IFN-gamma and IL-2 production (PubMed:21078852). Human CD4+ T-cells probably use TLR1/TLR2 heterodimers to respond to mycobacterial lipoproteins (PubMed:21078852). Acting via TLR2 enhances expression of host peroxisome proliferator-activated receptor gamma (PPARG), a regulator of inflammation and immunoregulation, and increases p38 MAPK phosphorylation, IL-6 and TNF-alpha expression (PubMed:25504154). Native or nonlipidated recombinant protein missing the first 4 residues have been shown to induce apoptosis in the human macrophage cell line THP-1 and human monocyte-derived macrophages in a TLR2, caspase-3 and caspase-8-dependent manner (PubMed:12594264). Protein overexpressed in M.smegmatis (lipidated and probably glycosylated) induces apoptosis in human macrophages via TLR2 in a caspase-3/caspase-8-mediated manner, but also in a caspase-independent manner where mitochondrial apoptosis-inducing factor (AIFM1) translocates to the nucleus (PubMed:23316255). Another study found mature, native (lipidated) protein did not induce apoptosis in THP-1 macrophage cell line (PubMed:12874328). Functions as an adhesin, binds to human and mouse macrophages (PubMed:25359607). {ECO:0000269|PubMed:10426995, ECO:0000269|PubMed:11160304, ECO:0000269|PubMed:11441098, ECO:0000269|PubMed:12594264, ECO:0000269|PubMed:12874328, ECO:0000269|PubMed:16177361, ECO:0000269|PubMed:16622205, ECO:0000269|PubMed:21078852, ECO:0000269|PubMed:23316255, ECO:0000269|PubMed:25359607, ECO:0000269|PubMed:25504154}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:25041568, ECO:0000305}; Lipid-anchor {ECO:0000305|PubMed:1906192}. Secreted, cell wall {ECO:0000269|PubMed:10426995, ECO:0000269|PubMed:16098710}. Cell surface {ECO:0000269|PubMed:25041568, ECO:0000269|PubMed:25359607}. Secreted {ECO:0000269|PubMed:16098710, ECO:0000305|PubMed:1906192}. Extracellular vesicle, bacterial extracellular vesicle {ECO:0000269|PubMed:21364279}. Host cytoplasm {ECO:0000269|PubMed:11123323}. Note=A soluble cell wall-associated protein (PubMed:10426995). Also found in culture filtrate in increasing quantities during growth (PubMed:1906192, PubMed:16098710). Following infection of mouse macrophage cell line J774A.1 with live (but not heat-killed) bacteria the protein is released in host cytoplasm at 1 hr but decreases dramatically by 3 hrs: release into the host requires protein lipidation and traffics from the immature phagosome through the host class I MHC antigen peptide presentation pathway (PubMed:11123323). Present in bacterial extracytoplasmic vesicles, both in mouse macrophages and in culture media (PubMed:21364279). Immunoelectron microscopy indicates this protein is close to the cell surface (PubMed:25041568). {ECO:0000269|PubMed:10426995, ECO:0000269|PubMed:11123323, ECO:0000269|PubMed:16098710, ECO:0000269|PubMed:1906192, ECO:0000269|PubMed:21364279, ECO:0000269|PubMed:25041568}.

Induction: Expressed in cell culture; expressed at a steady level for 4 days following infection of human mononuclear phagocytes. {ECO:0000269|PubMed:16177361}.

Domain: Forms a U-shaped beta-half-barrel with a large hydrophobic cavity. {ECO:0000305|Ref.25}.

Domain: A fragment of the mature protein (residues 41-60) prevents uptake of M.tuberculosis by a human macrophage-like cell line; lesser effects are seen on bacterial uptake by a human lung epithelial cell line. {ECO:0000269|PubMed:25041568}.

Ptm: Triacylated with a thioether-linked diacylglycerol with C16 and C19 on Cys-22 and an amide-linked C16 fatty acid (PubMed:24093492). Modified by Lgt on Cys-22 with an S-linked diacylglycerol with a mixture of C16, C18 and C19 fatty acids (palmitic, stearic and tuberculostearic acid), signal peptide is removed by LspA, modifed by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis (PubMed:24093492). Upon expression in M.smegmatis the protein is glycosylated (possibly by mannose, detected by concanavalin A (conA) binding) within the first 20 residues of the mature protein; altering the probably glycosylated Thr residues alters processing of the mature protein in M.smegmatis and slightly differently in M.vaccae (PubMed:8670858). Glycosylation may protect this region of the protein from proteolysis, which would release the lipoprotein from the cell surface (PubMed:8670858). Mannosylated upon expression in M.smegmatis; treatment with alpha-D-mannosidase decreases its apparent molecular weight (PubMed:16098710). Native protein binds conA (PubMed:16098710). {ECO:0000269|PubMed:16098710, ECO:0000269|PubMed:24093492, ECO:0000269|PubMed:8670858}.

Mass spectrometry: Mass=17300; Method=MALDI; Note=Expressed in M.bovis, lipidated.; Evidence={ECO:0000269|PubMed:24093492};

Disruption phenotype: No visible phenotype in culture. Grows less well than wild-type in human monocyte-derived macrophages (MDM) over 7 days; increased human monocyte MHC class II expression, decreased interleukin 1-beta secretion from monocytes and MDM (PubMed:16177361). No growth in C57BL/6 mice over 40 days, even in mice lacking gamma interferon (PubMed:17804126). {ECO:0000269|PubMed:16177361, ECO:0000269|PubMed:17804126}.

Biotechnology: A disrupted strain immunizes mice against subsequent infection with wild-type H37Rv as well as the M.bovis vaccine strain BCG. {ECO:0000269|PubMed:17804126}.

Similarity: Belongs to the mycobacterial 19 kDa antigen family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
Taxonomy:		Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex.



Function:		Based on its structure might be involved in ligand transport (Ref.25) (By similarity). {ECO:0000250\|UniProtKB:P65307, ECO:0000305\|Ref.25}.



Function:		A host TLR2 agonist (PubMed:10426995, PubMed:11441098, PubMed:12874328). Plays a complicated role in bacterial interactions with the host immune system; some effects favor the host (induces interleukin 1-beta and IL-12 p40 (IL12B), both increase the host's immune response) while others favor the bacteria (increases growth in monocyte-derived macrophages and decreases host MHC class II (MHC-II) expression and antigen processing) (PubMed:16177361). Induces host (human and mouse) IL-12 p40 (IL12B, a proinflammatory cytokine) release by monocyte cell lines via TLR2 and CD14 (PubMed:10426995). Induces host (human) monocytes to produce TNF-alpha, IL-6 and IL-12 p40; LpqH is a more potent inducer than PstS1 (PubMed:16622205). Inhibits MHC-II expression and antigen processing in host (mouse) macrophages via TLR2 (independently of TLR4) probably via the lipid modification (PubMed:11441098). Stimulates host (human) dendritic cell maturation to become MHC-II-positive antigen presenting cells via TLR2, which depends on lipidation; nonlipidated protein does not stimulate maturation (PubMed:11160304). Inhibits host (human and mouse) IFN-gamma signaling in macrophages via TLR2; decreases IFN-gamma stimulated MHC-II antigen processing as well as decreasing IFN-gamma-mediated up-regulation of immunoglobulin gamma Fc receptor (FCGR1A), enabling the bacteria to evade the immune system (PubMed:12874328). In resting human CD4+ T- cells lipidated (but probably not nonlipidated protein) is a costimulatory ligand (with anti-CD3 and anti-CD28) for T-cell proliferation and IFN-gamma and IL-2 production (PubMed:21078852). Human CD4+ T-cells probably use TLR1/TLR2 heterodimers to respond to mycobacterial lipoproteins (PubMed:21078852). Acting via TLR2 enhances expression of host peroxisome proliferator-activated receptor gamma (PPARG), a regulator of inflammation and immunoregulation, and increases p38 MAPK phosphorylation, IL-6 and TNF-alpha expression (PubMed:25504154). Native or nonlipidated recombinant protein missing the first 4 residues have been shown to induce apoptosis in the human macrophage cell line THP-1 and human monocyte-derived macrophages in a TLR2, caspase-3 and caspase-8-dependent manner (PubMed:12594264). Protein overexpressed in M.smegmatis (lipidated and probably glycosylated) induces apoptosis in human macrophages via TLR2 in a caspase-3/caspase-8-mediated manner, but also in a caspase-independent manner where mitochondrial apoptosis-inducing factor (AIFM1) translocates to the nucleus (PubMed:23316255). Another study found mature, native (lipidated) protein did not induce apoptosis in THP-1 macrophage cell line (PubMed:12874328). Functions as an adhesin, binds to human and mouse macrophages (PubMed:25359607). {ECO:0000269\|PubMed:10426995, ECO:0000269\|PubMed:11160304, ECO:0000269\|PubMed:11441098, ECO:0000269\|PubMed:12594264, ECO:0000269\|PubMed:12874328, ECO:0000269\|PubMed:16177361, ECO:0000269\|PubMed:16622205, ECO:0000269\|PubMed:21078852, ECO:0000269\|PubMed:23316255, ECO:0000269\|PubMed:25359607, ECO:0000269\|PubMed:25504154}.


Subcellular location:		Cell membrane {ECO:0000269\|PubMed:25041568, ECO:0000305}; Lipid-anchor {ECO:0000305\|PubMed:1906192}. Secreted, cell wall {ECO:0000269\|PubMed:10426995, ECO:0000269\|PubMed:16098710}. Cell surface {ECO:0000269\|PubMed:25041568, ECO:0000269\|PubMed:25359607}. Secreted {ECO:0000269\|PubMed:16098710, ECO:0000305\|PubMed:1906192}. Extracellular vesicle, bacterial extracellular vesicle {ECO:0000269\|PubMed:21364279}. Host cytoplasm {ECO:0000269\|PubMed:11123323}. Note=A soluble cell wall-associated protein (PubMed:10426995). Also found in culture filtrate in increasing quantities during growth (PubMed:1906192, PubMed:16098710). Following infection of mouse macrophage cell line J774A.1 with live (but not heat-killed) bacteria the protein is released in host cytoplasm at 1 hr but decreases dramatically by 3 hrs: release into the host requires protein lipidation and traffics from the immature phagosome through the host class I MHC antigen peptide presentation pathway (PubMed:11123323). Present in bacterial extracytoplasmic vesicles, both in mouse macrophages and in culture media (PubMed:21364279). Immunoelectron microscopy indicates this protein is close to the cell surface (PubMed:25041568). {ECO:0000269\|PubMed:10426995, ECO:0000269\|PubMed:11123323, ECO:0000269\|PubMed:16098710, ECO:0000269\|PubMed:1906192, ECO:0000269\|PubMed:21364279, ECO:0000269\|PubMed:25041568}.
Induction:		Expressed in cell culture; expressed at a steady level for 4 days following infection of human mononuclear phagocytes. {ECO:0000269\|PubMed:16177361}.
Domain:		Forms a U-shaped beta-half-barrel with a large hydrophobic cavity. {ECO:0000305\|Ref.25}.
Domain:		A fragment of the mature protein (residues 41-60) prevents uptake of M.tuberculosis by a human macrophage-like cell line; lesser effects are seen on bacterial uptake by a human lung epithelial cell line. {ECO:0000269\|PubMed:25041568}.
Ptm:		Triacylated with a thioether-linked diacylglycerol with C16 and C19 on Cys-22 and an amide-linked C16 fatty acid (PubMed:24093492). Modified by Lgt on Cys-22 with an S-linked diacylglycerol with a mixture of C16, C18 and C19 fatty acids (palmitic, stearic and tuberculostearic acid), signal peptide is removed by LspA, modifed by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis (PubMed:24093492). Upon expression in M.smegmatis the protein is glycosylated (possibly by mannose, detected by concanavalin A (conA) binding) within the first 20 residues of the mature protein; altering the probably glycosylated Thr residues alters processing of the mature protein in M.smegmatis and slightly differently in M.vaccae (PubMed:8670858). Glycosylation may protect this region of the protein from proteolysis, which would release the lipoprotein from the cell surface (PubMed:8670858). Mannosylated upon expression in M.smegmatis; treatment with alpha-D-mannosidase decreases its apparent molecular weight (PubMed:16098710). Native protein binds conA (PubMed:16098710). {ECO:0000269\|PubMed:16098710, ECO:0000269\|PubMed:24093492, ECO:0000269\|PubMed:8670858}.
Mass spectrometry:		Mass=17300; Method=MALDI; Note=Expressed in M.bovis, lipidated.; Evidence={ECO:0000269\|PubMed:24093492};
Disruption phenotype:		No visible phenotype in culture. Grows less well than wild-type in human monocyte-derived macrophages (MDM) over 7 days; increased human monocyte MHC class II expression, decreased interleukin 1-beta secretion from monocytes and MDM (PubMed:16177361). No growth in C57BL/6 mice over 40 days, even in mice lacking gamma interferon (PubMed:17804126). {ECO:0000269\|PubMed:16177361, ECO:0000269\|PubMed:17804126}.
Biotechnology:		A disrupted strain immunizes mice against subsequent infection with wild-type H37Rv as well as the M.bovis vaccine strain BCG. {ECO:0000269\|PubMed:17804126}.
Similarity:		Belongs to the mycobacterial 19 kDa antigen family. {ECO:0000305}.