ESPA_MYCTU
ID ESPA_MYCTU Reviewed; 392 AA.
AC P9WJE1; L0TDB5; O06267; Q7D572;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 34.
DE RecName: Full=ESX-1 secretion-associated protein EspA {ECO:0000305};
GN Name=espA {ECO:0000303|PubMed:16030141}; OrderedLocusNames=Rv3616c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION IN VIRULENCE, SUBCELLULAR
RP LOCATION, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=16030141; DOI=10.1073/pnas.0504922102;
RA Fortune S.M., Jaeger A., Sarracino D.A., Chase M.R., Sassetti C.M.,
RA Sherman D.R., Bloom B.R., Rubin E.J.;
RT "Mutually dependent secretion of proteins required for mycobacterial
RT virulence.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:10676-10681(2005).
RN [3]
RP REGULATION BY PHOP/PHOR.
RC STRAIN=H37Rv;
RX PubMed=16573683; DOI=10.1111/j.1365-2958.2006.05102.x;
RA Walters S.B., Dubnau E., Kolesnikova I., Laval F., Daffe M., Smith I.;
RT "The Mycobacterium tuberculosis PhoPR two-component system regulates genes
RT essential for virulence and complex lipid biosynthesis.";
RL Mol. Microbiol. 60:312-330(2006).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17604718; DOI=10.1016/j.cell.2007.05.059;
RA van der Wel N., Hava D., Houben D., Fluitsma D., van Zon M., Pierson J.,
RA Brenner M., Peters P.J.;
RT "M. tuberculosis and M. leprae translocate from the phagolysosome to the
RT cytosol in myeloid cells.";
RL Cell 129:1287-1298(2007).
RN [5]
RP REGULATION BY ESPR.
RX PubMed=18685700; DOI=10.1038/nature07219;
RA Raghavan S., Manzanillo P., Chan K., Dovey C., Cox J.S.;
RT "Secreted transcription factor controls Mycobacterium tuberculosis
RT virulence.";
RL Nature 454:717-721(2008).
RN [6]
RP SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=19854905; DOI=10.1128/jb.01032-09;
RA Callahan B., Nguyen K., Collins A., Valdes K., Caplow M., Crossman D.K.,
RA Steyn A.J., Eisele L., Derbyshire K.M.;
RT "Conservation of structure and protein-protein interactions mediated by the
RT secreted mycobacterial proteins EsxA, EsxB, and EspA.";
RL J. Bacteriol. 192:326-335(2010).
RN [7]
RP SUBUNIT, DISULFIDE BOND, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-138.
RX PubMed=20585630; DOI=10.1371/journal.ppat.1000957;
RA Garces A., Atmakuri K., Chase M.R., Woodworth J.S., Krastins B.,
RA Rothchild A.C., Ramsdell T.L., Lopez M.F., Behar S.M., Sarracino D.A.,
RA Fortune S.M.;
RT "EspA acts as a critical mediator of ESX1-dependent virulence in
RT Mycobacterium tuberculosis by affecting bacterial cell wall integrity.";
RL PLoS Pathog. 6:E1000957-E1000957(2010).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [9]
RP SUBCELLULAR LOCATION.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman, and H37Rv;
RX PubMed=22155774; DOI=10.1128/jb.06417-11;
RA Chen J.M., Boy-Roettger S., Dhar N., Sweeney N., Buxton R.S., Pojer F.,
RA Rosenkrands I., Cole S.T.;
RT "EspD is critical for the virulence-mediating ESX-1 secretion system in
RT Mycobacterium tuberculosis.";
RL J. Bacteriol. 194:884-893(2012).
RN [10]
RP REGULATION BY ESPR.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=22389481; DOI=10.1128/jb.00142-12;
RA Hunt D.M., Sweeney N.P., Mori L., Whalan R.H., Comas I., Norman L.,
RA Cortes T., Arnvig K.B., Davis E.O., Stapleton M.R., Green J., Buxton R.S.;
RT "Long-range transcriptional control of an operon necessary for virulence-
RT critical ESX-1 secretion in Mycobacterium tuberculosis.";
RL J. Bacteriol. 194:2307-2320(2012).
RN [11]
RP REGULATION BY MPRA/MPRB.
RC STRAIN=H37Rv;
RX PubMed=23104803; DOI=10.1128/jb.01067-12;
RA Pang X., Samten B., Cao G., Wang X., Tvinnereim A.R., Chen X.L.,
RA Howard S.T.;
RT "MprAB regulates the espA operon in Mycobacterium tuberculosis and
RT modulates ESX-1 function and host cytokine response.";
RL J. Bacteriol. 195:66-75(2013).
RN [12]
RP FUNCTION, AND MUTAGENESIS OF PHE-5; LYS-41; PHE-50; TRP-55; GLY-57 AND
RP LYS-62.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman, and H37Rv;
RX PubMed=24078612; DOI=10.1128/jb.00967-13;
RA Chen J.M., Zhang M., Rybniker J., Basterra L., Dhar N., Tischler A.D.,
RA Pojer F., Cole S.T.;
RT "Phenotypic profiling of Mycobacterium tuberculosis EspA point mutants
RT reveals that blockage of ESAT-6 and CFP-10 secretion in vitro does not
RT always correlate with attenuation of virulence.";
RL J. Bacteriol. 195:5421-5430(2013).
RN [13]
RP TRANSCRIPTIONAL REGULATION.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX PubMed=25536998; DOI=10.1099/mic.0.000023;
RA Cao G., Howard S.T., Zhang P., Wang X., Chen X.L., Samten B., Pang X.;
RT "EspR, a regulator of the ESX-1 secretion system in Mycobacterium
RT tuberculosis, is directly regulated by the two-component systems MprAB and
RT PhoPR.";
RL Microbiology 161:477-489(2015).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX PubMed=26048138; DOI=10.1016/j.chom.2015.05.003;
RA Wassermann R., Gulen M.F., Sala C., Perin S.G., Lou Y., Rybniker J.,
RA Schmid-Burgk J.L., Schmidt T., Hornung V., Cole S.T., Ablasser A.;
RT "Mycobacterium tuberculosis differentially activates cGAS- and
RT inflammasome-dependent intracellular immune responses through ESX-1.";
RL Cell Host Microbe 17:799-810(2015).
CC -!- FUNCTION: Required for secretion of EsxA (ESAT-6) and EsxB (CFP-10) and
CC for virulence. Involved in translocation of bacteria from the host
CC (human) phagolysosome to the host cytoplasm (PubMed:17604718).
CC {ECO:0000269|PubMed:16030141, ECO:0000269|PubMed:17604718,
CC ECO:0000269|PubMed:24078612}.
CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:20585630). An artificial
CC EsxB-EsxA heterodimer interacts with EspA (PubMed:19854905).
CC {ECO:0000269|PubMed:19854905, ECO:0000269|PubMed:20585630}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:16030141,
CC ECO:0000269|PubMed:20585630, ECO:0000269|PubMed:22155774}.
CC Note=Secreted via the ESX-1 / type VII secretion system (T7SS)
CC (PubMed:16030141). Secretion of EspA, EsxA and EsxB is mutually
CC dependent (PubMed:16030141). {ECO:0000269|PubMed:16030141}.
CC -!- INDUCTION: Transcriptionally activated by EspR (PubMed:18685700,
CC PubMed:22389481, PubMed:25536998). Repressed by the MprB/MprA two-
CC component system, by direct regulation and via EspR (PubMed:23104803,
CC PubMed:25536998). Up-regulated by the PhoP/PhoR two-component system,
CC via EspR (PubMed:16573683, PubMed:25536998).
CC {ECO:0000269|PubMed:16573683, ECO:0000269|PubMed:18685700,
CC ECO:0000269|PubMed:22389481, ECO:0000269|PubMed:23104803,
CC ECO:0000269|PubMed:25536998}.
CC -!- DISRUPTION PHENOTYPE: Deletion mutants fail to secrete EsxA and EsxB,
CC and are as attenuated as ESX-1 mutants in virulence assays
CC (PubMed:16030141). Bacteria no longer translocate from the
CC phagolysosome to the cytosol of host (human) cells; bacteria replicate
CC in phagolysosome (PubMed:17604718). Host (human) cells no longer
CC produce cytokine IP-10 (CXCL10) upon infection, but continue to produce
CC IL-1 beta (IL1B) (PubMed:26048138). {ECO:0000269|PubMed:16030141,
CC ECO:0000269|PubMed:17604718, ECO:0000269|PubMed:26048138}.
CC -!- MISCELLANEOUS: Maintenance of wild-type levels of EspA requires both
CC EspC and EspD. {ECO:0000269|PubMed:22155774}.
CC -!- MISCELLANEOUS: Has been postulated to mediate virulence through
CC maintenance of mycobacterial cell surface integrity (PubMed:20585630),
CC but studies of detergent sensitivity of various strains and mutants
CC indicate that EspACD and ESX-1 deficiency does not impact the cell
CC surface integrity (PubMed:24078612). {ECO:0000305|PubMed:20585630,
CC ECO:0000305|PubMed:24078612}.
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DR EMBL; AL123456; CCP46439.1; -; Genomic_DNA.
DR PIR; A70957; A70957.
DR RefSeq; NP_218133.1; NC_000962.3.
DR RefSeq; WP_003912265.1; NZ_NVQJ01000056.1.
DR AlphaFoldDB; P9WJE1; -.
DR IntAct; P9WJE1; 1.
DR STRING; 83332.Rv3616c; -.
DR PaxDb; P9WJE1; -.
DR DNASU; 885377; -.
DR GeneID; 885377; -.
DR KEGG; mtu:Rv3616c; -.
DR TubercuList; Rv3616c; -.
DR eggNOG; ENOG5031E2U; Bacteria.
DR OMA; LEEVWEF; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005576; C:extracellular region; IDA:MTBBASE.
DR GO; GO:0005615; C:extracellular space; IDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0071766; P:Actinobacterium-type cell wall biogenesis; IDA:MTBBASE.
DR GO; GO:0051701; P:biological process involved in interaction with host; IDA:MTBBASE.
DR GO; GO:0044315; P:protein secretion by the type VII secretion system; IMP:MTBBASE.
DR InterPro; IPR043796; ESX-1_EspA/EspE-like.
DR Pfam; PF18879; EspA_EspE; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Reference proteome; Secreted; Virulence.
FT CHAIN 1..392
FT /note="ESX-1 secretion-associated protein EspA"
FT /id="PRO_0000393903"
FT REGION 302..392
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT DISULFID 138
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:20585630"
FT MUTAGEN 5
FT /note="F->R: Severely destabilizes EspA and blocks ESX-1
FT secretion in vitro, but does not impact the cytotoxicity in
FT cellular models of infection. Can induce pro-inflammatory
FT responses in THP-1 cells and is as virulent as wild-type
FT during the acute phase of infection in mice."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 41
FT /note="K->A: Severely destabilizes EspA and blocks ESX-1
FT secretion in vitro, but does not impact the cytotoxicity in
FT cellular models of infection. Can induce pro-inflammatory
FT responses in THP-1 cells and is as virulent as wild-type
FT during the acute phase of infection in mice."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 50
FT /note="F->R: Severely destabilizes EspA and blocks ESX-1
FT secretion in vitro. Attenuated in cellular models of
FT tuberculosis infection."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 55
FT /note="W->R: Impairs EsxA and EsxB secretion in vitro.
FT Modest impact on EspD stability and secretion. Attenuated
FT in cellular models of tuberculosis infection."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 57
FT /note="G->R: Impairs EsxA and EsxB secretion in vitro.
FT Modest impact on EspD stability and secretion. Attenuated
FT in cellular models of tuberculosis infection."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 62
FT /note="K->A: Severely destabilizes EspA and blocks ESX-1
FT secretion in vitro. Attenuated in cellular models of
FT tuberculosis infection."
FT /evidence="ECO:0000269|PubMed:24078612"
FT MUTAGEN 138
FT /note="C->A: Does not affect secretion, but inhibits
FT disulfide bond formation. Alters mycobacterial cell wall
FT integrity and significantly attenuates virulence."
FT /evidence="ECO:0000269|PubMed:20585630"
SQ SEQUENCE 392 AA; 39888 MW; 82BBA8DD99D6F567 CRC64;
MSRAFIIDPT ISAIDGLYDL LGIGIPNQGG ILYSSLEYFE KALEELAAAF PGDGWLGSAA
DKYAGKNRNH VNFFQELADL DRQLISLIHD QANAVQTTRD ILEGAKKGLE FVRPVAVDLT
YIPVVGHALS AAFQAPFCAG AMAVVGGALA YLVVKTLINA TQLLKLLAKL AELVAAAIAD
IISDVADIIK GTLGEVWEFI TNALNGLKEL WDKLTGWVTG LFSRGWSNLE SFFAGVPGLT
GATSGLSQVT GLFGAAGLSA SSGLAHADSL ASSASLPALA GIGGGSGFGG LPSLAQVHAA
STRQALRPRA DGPVGAAAEQ VGGQSQLVSA QGSQGMGGPV GMGGMHPSSG ASKGTTTKKY
SEGAAAGTED AERAPVEADA GGGQKVLVRN VV
