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Function

A secreted protein that plays a number of roles in modulating the host's immune response to infection as well as being responsible for bacterial escape into the host cytoplasm. Acts as a strong host (human) T-cell antigen (PubMed:7729876, PubMed:11940590). Inhibits IL-12 p40 (IL12B) and TNF-alpha expression by infected host (mouse) macrophages, reduces the nitric oxide response by about 75% (PubMed:14557536). In mice previously exposed to the bacterium, elicits high level of IFN-gamma production by T-cells upon subsequent challenge by M.tuberculosis, in the first phase of a protective immune response (PubMed:7897219, PubMed:7729876). Higher levels (1.6-3.3 uM) of recombinant protein inhibit IFN-gamma production by host (human) T-cells and also IL-17 and TNF-alpha production but not IL-2; decreases expression of host ATF-2 and JUN transcription factors by affecting T-cell receptors signaling downstream of ZAP70, without cytotoxicity or apoptosis (PubMed:19265145). EsxA inhibits IFN-gamma production in human T-cells by activating p38 MAPK (MAPK14), p38 MAPK is not responsible for IL-17 decrease (PubMed:21586573). Binds host (mouse) Toll-like receptor 2 (TLR2) and decreases host MYD88-dependent signaling; binding to TLR2 activates host kinase AKT and subsequently inhibits downstream activation of NF-kappa-B; the C-terminal 20 residues (76-95) are necessary and sufficient for the TLR2 inhibitory effect (PubMed:17486091). Required for induction of host (human) IL-1B maturation and release by activating the host NLRP3/ASC inflammasome; may also promote access of other tuberculosis proteins to the host cells cytoplasm (PubMed:20148899). Induces IL-8 (CXCL8) expression in host (human) lung epithelial cells (PubMed:23867456). Exogenously applied protein, or protein expressed in host (human and mouse), binds beta-2-microglobulin (B2M) and decreases its export to the cell surface, probably leading to defects in class I antigen presentation by the host cell (PubMed:25356553). Responsible for mitochondrial fragmention, redistribution around the cell nucleus and decreased mitochondrial mass; this effect is not seen until 48 hours post-infection (PubMed:26092385). Able to disrupt artificial planar bilayers in the absence of EsxB (CFP-10) (PubMed:14557547). Native protein binds artificial liposomes in the absence but not presence of EsxB and is able to rigidify and lyse them; the EsxA-EsxB complex dissociates at acidic pH, EsxB might serve as a chaperone to prevent membrane lysis (PubMed:17557817). Recombinant protein induces leakage of phosphocholine liposomes at acidic pH in the absence of ExsB, undergoes conformational change, becoming more alpha-helical at acidic pH (PubMed:23150662, PubMed:25645924). The study using recombinant protein did not find dissociation of EsxA-EsxB complex at acidic pH (PubMed:23150662). Involved in translocation of bacteria from the host (human) phagolysosome to the host cytoplasm (PubMed:17604718, PubMed:22319448). Translocation into host cytoplasm is visible 3 days post-infection using cultured human cells and precedes host cell death (PubMed:22319448). Recombinant protein induces apoptosis in host (human) differentiated cell lines, which is cell-line dependent; bacteria missing the ESX-1 locus do not induce apoptosis (PubMed:17298391). Host (human) cells treated with EsxA become permeable to extracellular dye (PubMed:17298391). EsxA and EsxA-EsxB are cytotoxic to pneumocytes (PubMed:19906174). ESX-1 secretion system-induced host (mouse) cell apoptosis, which is probably responsible for infection of new host cells, might be due to EsxA (PubMed:23848406). EsxA induces necrosis in aged neutrophils (PubMed:25321481). May help regulate assembly and function of the type VII secretion system (T7SS) (By similarity). EsxA disassembles pre-formed EccC-EsxB multimers, possibly by making EccC-EsxA-EsxB trimers instead of EccC-EsxB-EsxB-EccC tetramers (By similarity). {ECO:0000250|UniProtKB:D1A4H1, ECO:0000269|PubMed:11940590, ECO:0000269|PubMed:14557536, ECO:0000269|PubMed:14557547, ECO:0000269|PubMed:17298391, ECO:0000269|PubMed:17486091, ECO:0000269|PubMed:17557817, ECO:0000269|PubMed:17604718, ECO:0000269|PubMed:19265145, ECO:0000269|PubMed:19906174, ECO:0000269|PubMed:20148899, ECO:0000269|PubMed:21586573, ECO:0000269|PubMed:22319448, ECO:0000269|PubMed:23867456, ECO:0000269|PubMed:25321481, ECO:0000269|PubMed:25356553, ECO:0000269|PubMed:26092385, ECO:0000269|PubMed:26260636, ECO:0000269|PubMed:7729876, ECO:0000269|PubMed:7897219, ECO:0000305|PubMed:23848406}.; FUNCTION: May be critical in pro-bacteria versus pro-host interactions; ESX-1 mediates DNA mediated export (maybe via EsxA). The DNA interacts with host (human) cGAS, leading to cGAMP production and activation of the host STING-TBK-1-IRF-3 signaling pathway that leads to IFN-beta which is thought to be "pro-bacteria". Mycobacterial dsDNA also interacts with AIM2-NLRP3-ASC to activate an inflammasome, leading to the "pro-host" IL-1-beta (PubMed:26048138, PubMed:26048136). {ECO:0000269|PubMed:26048136, ECO:0000269|PubMed:26048138}.

Family

WXG100 family, ESAT-6 subfamily

GO

• protein secretion by the type VII secretion system GO:0044315 biological_process
• host cell surface binding GO:0046812 molecular_function
• host cell surface GO:0044228 cellular_component
• host cell endoplasmic reticulum GO:0044165 cellular_component
• host cell plasma membrane GO:0020002 cellular_component
• pathogenesis GO:0009405 biological_process
• cell wall GO:0005618 cellular_component
• extracellular region GO:0005576 cellular_component
• protein homodimerization activity GO:0042803 molecular_function
• plasma membrane GO:0005886 cellular_component
• modulation by symbiont of host signal transduction pathway GO:0052027 biological_process
• negative regulation by symbiont of host cell-mediated immune response GO:0052083 biological_process
• cytoplasm GO:0005737 cellular_component
• integral component of membrane GO:0016021 cellular_component

InterPro

• IPR036689
• IPR010310

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UniProt

P9WNK7

GenBank

Rv3875

EnsemblBacteria

Rv3875

Mycobrowser

Rv3875

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Rv3875 doesn't seem to be a targeted by any drug.

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  Tuberculosis mtu05152

  mtu05152

  Human Diseases; Infectious disease: bacterial