PG33_MYCTU
ID PG33_MYCTU Reviewed; 498 AA.
AC P9WIF5; L0TAP6; Q50615;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 38.
DE RecName: Full=PE-PGRS family protein PE_PGRS33 {ECO:0000305};
GN Name=PE_PGRS33 {ECO:0000312|EMBL:CCP44584.1};
GN OrderedLocusNames=Rv1818c {ECO:0000312|EMBL:CCP44584.1};
GN ORFNames=MTCY1A11.25c;
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 BIOTECHNOLOGY, AND IMMUNE RESPONSE.
RX PubMed=11500435; DOI=10.1128/iai.69.9.5606-5611.2001;
RA Delogu G., Brennan M.J.;
RT "Comparative immune response to PE and PE_PGRS antigens of Mycobacterium
RT tuberculosis.";
RL Infect. Immun. 69:5606-5611(2001).
RN [3]
RP INDUCTION.
RX PubMed=11967065; DOI=10.1046/j.1365-2958.2002.02813.x;
RA Banu S., Honore N., Saint-Joanis B., Philpott D., Prevost M.C., Cole S.T.;
RT "Are the PE-PGRS proteins of Mycobacterium tuberculosis variable surface
RT antigens?";
RL Mol. Microbiol. 44:9-19(2002).
RN [4]
RP SUBCELLULAR LOCATION, AND DOMAIN.
RC STRAIN=H37Rv;
RX PubMed=15101979; DOI=10.1111/j.1365-2958.2004.04007.x;
RA Delogu G., Pusceddu C., Bua A., Fadda G., Brennan M.J., Zanetti S.;
RT "Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface
RT exposed and influences bacterial cell structure.";
RL Mol. Microbiol. 52:725-733(2004).
RN [5]
RP INDUCTION.
RX PubMed=16672626; DOI=10.1128/jb.188.10.3721-3725.2006;
RA Dheenadhayalan V., Delogu G., Sanguinetti M., Fadda G., Brennan M.J.;
RT "Variable expression patterns of Mycobacterium tuberculosis PE_PGRS genes:
RT evidence that PE_PGRS16 and PE_PGRS26 are inversely regulated in vivo.";
RL J. Bacteriol. 188:3721-3725(2006).
RN [6]
RP BIOTECHNOLOGY, AND INVOLVEMENT IN B-CELL RESPONSE.
RX PubMed=17687113; DOI=10.1128/cvi.00181-07;
RA Narayana Y., Joshi B., Katoch V.M., Mishra K.C., Balaji K.N.;
RT "Differential B-cell responses are induced by Mycobacterium tuberculosis PE
RT antigens Rv1169c, Rv0978c, and Rv1818c.";
RL Clin. Vaccine Immunol. 14:1334-1341(2007).
RN [7]
RP FUNCTION, INTERACTION WITH TLR2, AND DOMAIN.
RC STRAIN=H37Rv;
RX PubMed=17095513; DOI=10.1074/jbc.m604379200;
RA Basu S., Pathak S.K., Banerjee A., Pathak S., Bhattacharyya A., Yang Z.,
RA Talarico S., Kundu M., Basu J.;
RT "Execution of macrophage apoptosis by PE_PGRS33 of Mycobacterium
RT tuberculosis is mediated by Toll-like receptor 2-dependent release of tumor
RT necrosis factor-alpha.";
RL J. Biol. Chem. 282:1039-1050(2007).
RN [8]
RP FUNCTION IN INDUCTION OF APOPTOSIS, AND SUBCELLULAR LOCATION.
RC STRAIN=H37Rv;
RX PubMed=17223373; DOI=10.1016/j.micinf.2006.11.013;
RA Balaji K.N., Goyal G., Narayana Y., Srinivas M., Chaturvedi R.,
RA Mohammad S.;
RT "Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium
RT tuberculosis is regulated by mitochondrial intermediates in T cells.";
RL Microbes Infect. 9:271-281(2007).
RN [9]
RP SUBCELLULAR LOCATION, AND DOMAIN.
RX PubMed=18028308; DOI=10.1111/j.1365-2958.2007.06023.x;
RA Cascioferro A., Delogu G., Colone M., Sali M., Stringaro A., Arancia G.,
RA Fadda G., Palu G., Manganelli R.;
RT "PE is a functional domain responsible for protein translocation and
RT localization on mycobacterial cell wall.";
RL Mol. Microbiol. 66:1536-1547(2007).
RN [10]
RP SUBCELLULAR LOCATION, AND EXPRESSION IN M.SMEGMATIS.
RX PubMed=18957600; DOI=10.1099/mic.0.2008/019968-0;
RA Singh P.P., Parra M., Cadieux N., Brennan M.J.;
RT "A comparative study of host response to three Mycobacterium tuberculosis
RT PE_PGRS proteins.";
RL Microbiology 154:3469-3479(2008).
RN [11]
RP INDUCTION.
RX PubMed=19068228; DOI=10.1016/j.micpath.2008.11.003;
RA Vallecillo A.J., Espitia C.;
RT "Expression of Mycobacterium tuberculosis pe_pgrs33 is repressed during
RT stationary phase and stress conditions, and its transcription is mediated
RT by sigma factor A.";
RL Microb. Pathog. 46:119-127(2009).
RN [12]
RP SUBCELLULAR LOCATION, AND DOMAIN.
RX PubMed=21081760; DOI=10.1099/mic.0.041996-0;
RA Cadieux N., Parra M., Cohen H., Maric D., Morris S.L., Brennan M.J.;
RT "Induction of cell death after localization to the host cell mitochondria
RT by the Mycobacterium tuberculosis PE_PGRS33 protein.";
RL Microbiology 157:793-804(2011).
RN [13]
RP SUBCELLULAR LOCATION, EXPORT VIA ESX-5, AND DOMAIN.
RX PubMed=22110736; DOI=10.1371/journal.pone.0027713;
RA Cascioferro A., Daleke M.H., Ventura M., Dona V., Delogu G., Palu G.,
RA Bitter W., Manganelli R.;
RT "Functional dissection of the PE domain responsible for translocation of
RT PE_PGRS33 across the mycobacterial cell wall.";
RL PLoS ONE 6:E27713-E27713(2011).
RN [14]
RP FUNCTION, AND DOMAIN.
RC STRAIN=H37Rv;
RX PubMed=24106104; DOI=10.1111/2049-632x.12096;
RA Zumbo A., Palucci I., Cascioferro A., Sali M., Ventura M., D'Alfonso P.,
RA Iantomasi R., Di Sante G., Ria F., Sanguinetti M., Fadda G., Manganelli R.,
RA Delogu G.;
RT "Functional dissection of protein domains involved in the immunomodulatory
RT properties of PE_PGRS33 of Mycobacterium tuberculosis.";
RL Pathog. Dis. 69:232-239(2013).
RN [15]
RP BIOTECHNOLOGY, AND IMMUNE RESPONSE.
RX PubMed=24904584; DOI=10.3389/fimmu.2014.00236;
RA Cohen I., Parada C., Acosta-Gio E., Espitia C.;
RT "The PGRS domain from PE_PGRS33 of Mycobacterium tuberculosis is target of
RT humoral immune response in mice and humans.";
RL Front. Immunol. 5:236-236(2014).
RN [16]
RP REVIEW.
RX PubMed=25693607; DOI=10.1586/14760584.2015.1015995;
RA Gastelum-Avina P., Velazquez C., Espitia C., Lares-Villa F.,
RA Garibay-Escobar A.;
RT "A PE_PGRS33 protein of Mycobacterium tuberculosis: an ideal target for
RT future tuberculosis vaccine design.";
RL Expert Rev. Vaccines 14:699-711(2015).
RN [17]
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH TLR2, AND SUBCELLULAR
RP LOCATION.
RX PubMed=27483162; DOI=10.1021/acs.biochem.6b00289;
RA Yeruva V.C., Kulkarni A., Khandelwal R., Sharma Y., Raghunand T.R.;
RT "The PE_PGRS proteins of Mycobacterium tuberculosis are Ca(2+) binding
RT mediators of host-pathogen interaction.";
RL Biochemistry 55:4675-4687(2016).
RN [18]
RP FUNCTION, INTERACTION WITH TLR2, DOMAIN, AND DISRUPTION PHENOTYPE.
RX PubMed=26978522; DOI=10.1371/journal.pone.0150800;
RA Palucci I., Camassa S., Cascioferro A., Sali M., Anoosheh S., Zumbo A.,
RA Minerva M., Iantomasi R., De Maio F., Di Sante G., Ria F., Sanguinetti M.,
RA Palu G., Brennan M.J., Manganelli R., Delogu G.;
RT "PE_PGRS33 contributes to Mycobacterium tuberculosis entry in macrophages
RT through interaction with TLR2.";
RL PLoS ONE 11:E0150800-E0150800(2016).
CC -!- FUNCTION: Induces TNF-alpha release through human Toll-like receptor 2
CC (TLR2) signaling pathway, leading to macrophage apoptosis
CC (PubMed:17095513, PubMed:17223373, PubMed:24106104). The signaling
CC pathway involves TLR2-dependent activation of the mitogen-activated
CC protein kinase kinase kinase 5 (ASK1), which activates the p38 and JNK
CC MAPKs, leading to enhanced expression of TNF-alpha and tumor necrosis
CC factor receptor superfamily member 1A (TNFRI) genes. Signals are
CC amplified through classical caspase 8-dependent mitochondrial release
CC of cytochrome c, leading to the activation of caspases 9 and 3
CC (PubMed:17095513). Mediates Ca(2+)-dependent up-regulation of the anti-
CC inflammatory cytokine IL-10 (PubMed:27483162). Mediates entry into
CC macrophages in a TLR2-dependent mechanism and activates the TLR2-
CC dependent pro-adhesive pathway (PubMed:26978522).
CC {ECO:0000269|PubMed:17095513, ECO:0000269|PubMed:17223373,
CC ECO:0000269|PubMed:24106104, ECO:0000269|PubMed:26978522,
CC ECO:0000269|PubMed:27483162}.
CC -!- ACTIVITY REGULATION: Binding of Ca(2+) to PE_PGRS33 induces
CC conformational changes and increases affinity for TLR2.
CC {ECO:0000269|PubMed:27483162}.
CC -!- SUBUNIT: Interacts with human TLR2. {ECO:0000269|PubMed:17095513,
CC ECO:0000269|PubMed:26978522, ECO:0000269|PubMed:27483162}.
CC -!- SUBCELLULAR LOCATION: Secreted, cell wall {ECO:0000269|PubMed:15101979,
CC ECO:0000269|PubMed:18028308, ECO:0000269|PubMed:22110736,
CC ECO:0000269|PubMed:27483162}. Cell surface
CC {ECO:0000269|PubMed:15101979, ECO:0000269|PubMed:18028308,
CC ECO:0000269|PubMed:18957600, ECO:0000269|PubMed:22110736,
CC ECO:0000269|PubMed:27483162}. Cell outer membrane
CC {ECO:0000269|PubMed:18028308}. Note=Exported to the cell surface via
CC the ESX-5 / type VII secretion system (T7SS) (PubMed:22110736).
CC Localizes mostly at the cell poles (PubMed:15101979). Colocalizes to
CC mitochondria in transfected eukaryotic cells (PubMed:17223373,
CC PubMed:21081760). {ECO:0000269|PubMed:15101979,
CC ECO:0000269|PubMed:17223373, ECO:0000269|PubMed:21081760,
CC ECO:0000269|PubMed:22110736}.
CC -!- INDUCTION: Constitutively expressed in vitro, suggesting that it could
CC be an essential gene (PubMed:11967065, PubMed:16672626). Expression is
CC regulated by SigA. Down-regulated during stationary phase, under
CC nutrient starvation and oxygen depletion (PubMed:19068228).
CC {ECO:0000269|PubMed:11967065, ECO:0000269|PubMed:16672626,
CC ECO:0000269|PubMed:19068228}.
CC -!- DOMAIN: Contains an N-terminal PE domain, followed by a conserved
CC linker region and a C-terminal PGRS domain (PubMed:18028308,
CC PubMed:21081760). The PE domain is responsible for the export and
CC localization to the cell wall (PubMed:15101979, PubMed:18028308,
CC PubMed:22110736). The PGRS domain is required for TNF-alpha secretion
CC and is responsible for the main immunomodulatory properties of the
CC protein (PubMed:17095513, PubMed:24106104). Variations within the PGRS
CC domain alter the levels of TNF-alpha induction and are likely to have
CC an impact on the innate immune response (PubMed:17095513). PGRS domain
CC is also required to mediate cell entry into macrophages
CC (PubMed:26978522). Colocalization to the mitochondria of host cells is
CC dependent on the linker region and the PGRS domain, but not the PE
CC domain (PubMed:21081760). {ECO:0000269|PubMed:15101979,
CC ECO:0000269|PubMed:17095513, ECO:0000269|PubMed:18028308,
CC ECO:0000269|PubMed:21081760, ECO:0000269|PubMed:22110736,
CC ECO:0000269|PubMed:24106104, ECO:0000269|PubMed:26978522}.
CC -!- DISRUPTION PHENOTYPE: Deletion mutant is strongly impaired in its
CC ability to enter macrophages. Deletion does not affect the
CC intracellular growth in macrophages. {ECO:0000269|PubMed:26978522}.
CC -!- BIOTECHNOLOGY: PE domain induces protective cellular immune response
CC and PGRS domain induces humoral immune response during infection in
CC mice, suggesting that this protein is a promising candidate for the
CC development of M.tuberculosis vaccines (PubMed:11500435). Immunization
CC of mice with the PE_PGRS33 protein stimulated CD4(+) and CD8(+) T-cell
CC proliferation as well as IFN-gamma secretion, supporting the potential
CC use of PE_PGRS33 as a vaccine candidate for tuberculosis
CC (PubMed:24904584). Elicits a strong B-cell humoral response among
CC different clinical categories of both adult and child tuberculosis
CC patients, indicating that it could be used in the serodiagnosis of
CC tuberculosis (PubMed:17687113). {ECO:0000269|PubMed:11500435,
CC ECO:0000269|PubMed:17687113, ECO:0000269|PubMed:24904584}.
CC -!- MISCELLANEOUS: Expression of this gene in M.smegmatis leads to low
CC levels of NO and IL-12, increased level of IL-10 and better survival of
CC recombinant strains in macrophages. {ECO:0000269|PubMed:18957600}.
CC -!- SIMILARITY: Belongs to the mycobacterial PE family. PGRS subfamily.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AL123456; CCP44584.1; -; Genomic_DNA.
DR PIR; C70720; C70720.
DR RefSeq; WP_010886133.1; NZ_KK339370.1.
DR RefSeq; YP_177846.1; NC_000962.3.
DR AlphaFoldDB; P9WIF5; -.
DR STRING; 83332.Rv1818c; -.
DR PaxDb; P9WIF5; -.
DR GeneID; 885551; -.
DR KEGG; mtu:Rv1818c; -.
DR PATRIC; fig|83332.111.peg.2023; -.
DR TubercuList; Rv1818c; -.
DR eggNOG; COG0657; Bacteria.
DR OMA; MRTHISQ; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0009279; C:cell outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-KW.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; IDA:UniProtKB.
DR GO; GO:0046789; F:host cell surface receptor binding; IPI:MTBBASE.
DR GO; GO:0044650; P:adhesion of symbiont to host cell; IMP:UniProtKB.
DR GO; GO:0052167; P:modulation by symbiont of host innate immune response; IDA:MTBBASE.
DR GO; GO:0070482; P:response to oxygen levels; IEP:MTBBASE.
DR GO; GO:0042594; P:response to starvation; IEP:MTBBASE.
DR InterPro; IPR000084; PE-PGRS_N.
DR Pfam; PF00934; PE; 1.
PE 1: Evidence at protein level;
KW Calcium; Cell outer membrane; Cell wall; Membrane; Reference proteome;
KW Secreted; Virulence.
FT CHAIN 1..498
FT /note="PE-PGRS family protein PE_PGRS33"
FT /id="PRO_0000216164"
FT DOMAIN 1..93
FT /note="PE"
FT /evidence="ECO:0000255"
FT REGION 1..30
FT /note="Essential for translocation to the cell surface"
FT /evidence="ECO:0000269|PubMed:22110736"
FT REGION 140..260
FT /note="Interacts with TLR2"
FT /evidence="ECO:0000269|PubMed:26978522"
SQ SEQUENCE 498 AA; 40755 MW; 4F6F78F2482586BA CRC64;
MSFVVTIPEA LAAVATDLAG IGSTIGTANA AAAVPTTTVL AAAADEVSAA MAALFSGHAQ
AYQALSAQAA LFHEQFVRAL TAGAGSYAAA EAASAAPLEG VLDVINAPAL ALLGRPLIGN
GANGAPGTGA NGGDGGILIG NGGAGGSGAA GMPGGNGGAA GLFGNGGAGG AGGNVASGTA
GFGGAGGAGG LLYGAGGAGG AGGRAGGGVG GIGGAGGAGG NGGLLFGAGG AGGVGGLAAD
AGDGGAGGDG GLFFGVGGAG GAGGTGTNVT GGAGGAGGNG GLLFGAGGVG GVGGDGVAFL
GTAPGGPGGA GGAGGLFGVG GAGGAGGIGL VGNGGAGGSG GSALLWGDGG AGGAGGVGST
TGGAGGAGGN AGLLVGAGGA GGAGALGGGA TGVGGAGGNG GTAGLLFGAG GAGGFGFGGA
GGAGGLGGKA GLIGDGGDGG AGGNGTGAKG GDGGAGGGAI LVGNGGNGGN AGSGTPNGSA
GTGGAGGLLG KNGMNGLP
