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Cited by 50Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyEscherichia coli research studies

ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins

Open access
Vaziri, Farzam, Brosch, Roland·2019·Microbiology Spectrum
DOI 10.1128/microbiolspec.psib-0029-2019PMC PMC10957191
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Abstract

The causative agent of human tuberculosis, Mycobacterium tuberculosis , has a complex lipid-rich diderm envelope, which acts as a major barrier protecting the bacterium against the hostile environment inside the host cells. For the transfer of diverse molecules across this complex cell envelope, M. tuberculosis has a series of general and specialized protein secretion systems, characterized by the SecA general secretion pathway, the twin-arginine translocation pathway, and five specific ESX type VII secretion systems. In this review, we focus on the latter systems, known as ESX-1 to ESX-5, which were first discovered almost 20 years ago during the in silico analysis of the genome sequence of M. tuberculosis H37Rv. Since then, these systems have been the subject of highly dynamic research due to their involvement in several key biological processes and host-pathogen interactions of the tubercle bacilli.

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Crossref · 10.1128/microbiolspec.psib-0029-2019

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  • Premisecitation

    M. tuberculosis possesses five ESX/T7S systems, ESX-1 to ESX-5.

    “M. tuberculosis possesses five ESX/T7S systems (ESX-1 to ESX-5) (7,8,11,16).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] 7. Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R. 2004. ESAT- 6 proteins: protective antigens and virulence factors? Trends Microbiol 12:500-508. http://dx.doi.org/10.1016/j.tim.2004.09.007. source

      Not checked in the free run.

    • cites [8] 8. Abdallah AM, Gey van Pittius NC, Champion PA, Cox J, Luirink J, Vandenbroucke-Grauls CM, Appelmelk BJ, Bitter W. 2007. Type VII secretion-mycobacteria show the way. Nat Rev Microbiol 5:883-891. http://dx.doi.org/10.1038/nrmicro1773. source

      Not checked in the free run.

    • cites [11] 11. Gröschel MI, Sayes F, Simeone R, Majlessi L, Brosch R. 2016. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat Rev Microbiol 14:677-691. http://dx.doi.org/10.1038/nrmicro.2016.131. source

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  • Premisecitation

    Mycobacteria are surrounded by a diderm cell envelope consisting of an inner membrane, a peptidoglycan layer, an arabinogalactan layer, an outer mycomembrane made of covalently linked mycolic acids and extractable lipids, and a capsule.

    “Mycobacteria are surrounded by a diderm cell envelope, consisting of an inner membrane, a peptidoglycan layer, an arabinogalactan layer, an outer membrane, named mycomembrane, which is composed of covalently linked mycolic acids and extractable lipids, and a capsule (14,15).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] 14. Daffé M. 2015. The cell envelope of tubercle bacilli. Tuberculosis (Edinb) 95(Suppl 1):S155-S158. http://dx.doi.org/10.1016/j.tube.2015 .02.024. source

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    • cites [15] 15. Touchette MH, Seeliger JC. 2017. Transport of outer membrane lipids in mycobacteria. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1340- 1354. http://dx.doi.org/10.1016/j.bbalip.2017.01.005. source

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  • Premisecitation

    The M. bovis BCG vaccine has lost ESX-1 functions due to deletion of the region of difference RD1.

    “which is in line with the attenuation of”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] 65. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. 2002. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Myco- bacterium bovis BCG and Mycobacterium microti. Mol Microbiol 46:709-717. http://dx.doi.org/10.1046/j.1365-2958.2002.03237.x. source

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  • Premisecitation

    A certain flexibility of the cytosolic domains of EccC in interaction with effectors was suggested, which is different from the cognate ATPase in type IV secretion systems.

    “A certain flexibility of the cytosolic domains of EccC in interaction with effectors was suggested (10,40), which is different from the cognate ATPase in type IV secretion systems (10).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] 10. Beckham KS, Ciccarelli L, Bunduc CM, Mertens HD, Ummels R, Lugmayr W, Mayr J, Rettel M, Savitski MM, Svergun DI, Bitter W, Wilmanns M, Marlovits TC, Parret AH, Houben EN. 2017. Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis. Nat Microbiol 2:17047. http://dx.doi.org/10 .1038/nmicrobiol.2017.47. source

      Not checked in the free run.

    • cites [40] 40. Rosenberg OS, Dovala D, Li X, Connolly L, Bendebury A, Finer- Moore J, Holton J, Cheng Y, Stroud RM, Cox JS. 2015. Substrates control multimerization and activation of the multi-domain ATPase motor of type VII secretion. Cell 161:501-512. http://dx.doi.org/10.1016/j.cell.2015 .03.040. source

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  • Premisecitation

    The ESX-1 system is required for distributive conjugal transfer (DCT) of chromosomal DNA from donor into recipient strains of M. smegmatis.

    “For example, the ESX-1 system, which is present in fast-and slow-growing mycobacterial species, is required for distributive conjugal transfer (DCT) of chromosomal DNA from donor into recipient strains of M. smegmatis (51,52).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] 51. Coros A, Callahan B, Battaglioli E, Derbyshire KM. 2008. The spe- cialized secretory apparatus ESX-1 is essential for DNA transfer in Mycobacterium smegmatis. Mol Microbiol 69:794-808. http://dx.doi.org /10.1111/j.1365-2958.2008.06299.x. source

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    • cites [52] 52. Derbyshire KM, Gray TA. 2014. Distributive conjugal transfer: new insights into horizontal gene transfer and genetic exchange in myco- bacteria. Microbiol Spectr 2:MGM2-0022-2013. http://dx.doi.org/10 .1128/microbiolspec.MGM2-0022-2013. source

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  • Classified as probably not a substantial claim. 7
  • May combine two claims. 25

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ESX/T7S systems were first discovered almost 20 years ago during in silico analyses of the genome sequence and proteome of M. tuberculosis H37Rv.

    “which were first discovered almost 20 years ago during in silico analyses of the genome sequence and the proteome of Mycobacterium tuberculosis H37Rv (17,18).”
    • Also stated in: § Abstract · plain
      “which were first discovered almost 20 years ago during the in silico analysis of the genome sequence of M. tuberculosis H37Rv.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] 17. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, III, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deci- phering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537-544. http://dx.doi.org/10.10 source

      Not checked in the free run.

    • cites [18] 18. Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST. 1999. Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber Lung Dis 79:329-342. http://dx.doi.org/10.1054/tuld.1999.0220. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ESX/T7S systems are encoded in different sections of the mycobacterial chromosome and seem to have evolved by gene duplication and diversification from simpler systems shuffled around in actinobacterial and mycobacterial species, often mediated by plasmids encoding ESX/T7S elements and type IV secretion elements.

    “These systems, encoded in different sections of the mycobacterial chromosome, seem to have evolved by gene duplication and diversification from simpler systems that were shuffled around in different actinobacterial and mycobacterial species, often mediated by plasmids encoding ESX/T7S elements as well as elements of type IV secretion systems (21)(22)(23).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] 21. Dumas E, Christina Boritsch E, Vandenbogaert M, Rodríguez de la Vega RC, Thiberge JM, Caro V, Gaillard JL, Heym B, Girard-Misguich F, Brosch R, Sapriel G. 2016. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Genome Biol Evol 8:387-402. http://dx.doi.org/10.1093/gbe/evw001. source

      Not checked in the free run.

    • cites [22] 22. Newton-Foot M, Warren RM, Sampson SL, van Helden PD, Gey van Pittius NC. 2016. The plasmid-mediated evolution of the mycobacterial ESX (type VII) secretion systems. BMC Evol Biol 16:62. http://dx.doi.org /10.1186/s12862-016-0631-2. source

      Not checked in the free run.

    • cites [23] 23. Ummels R, Abdallah AM, Kuiper V, Aâjoud A, Sparrius M, Naeem R, Spaink HP, van Soolingen D, Pain A, Bitter W. 2014. Identification of a novel conjugative plasmid in mycobacteria that requires both type IV and type VII secretion. mBio 5:e01744-14. http://dx.doi.org/10.1128/mBio .01744-14. source

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    Premisecitation

    All five ESX systems share common features: small secreted proteins of about 100 amino acids with a conserved Trp-X-Gly (WXG) motif, an FtsK-SpoIIIE ATPase, several transmembrane proteins, and a subtilisin-like mycosin (MycP).

    “All five ESX systems share several common features: the presence of small secreted proteins (of about 100 amino acids) with a conserved Trp-X-Gly (WXG) motif (20), an FtsK-SpoIIIE ATPase, several transmembrane proteins, and a subtilisin-like mycosin (MycP) (11,16) (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] 20. Pallen MJ. 2002. The ESAT-6/WXG100 superfamily-and a new Gram-positive secretion system? Trends Microbiol 10:209-212. http://dx .doi.org/10.1016/S0966-842X(02)02345-4. source

      Not checked in the free run.

    • cites [11] 11. Gröschel MI, Sayes F, Simeone R, Majlessi L, Brosch R. 2016. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat Rev Microbiol 14:677-691. http://dx.doi.org/10.1038/nrmicro.2016.131. source

      Not checked in the free run.

    • cites [16] 16. Bitter W, Houben EN, Bottai D, Brodin P, Brown EJ, Cox JS, Derbyshire K, Fortune SM, Gao LY, Liu J, Gey van Pittius NC, Pym AS, Rubin EJ, Sherman DR, Cole ST, Brosch R. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5:e1000507. http://dx.doi.org/10.1371/journal.ppat.1000507. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M. tuberculosis has general and specialized protein secretion systems, including the SecA pathway, the twin-arginine translocation pathway, and five ESX type VII secretion systems.

    “This unusual cell envelope requires complex secretion systems for the export/secretion of proteins, such as those of the SecA and twin-arginine translocation pathways, as well as the specialized ESX/ T7S systems (7,8,16)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] 7. Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R. 2004. ESAT- 6 proteins: protective antigens and virulence factors? Trends Microbiol 12:500-508. http://dx.doi.org/10.1016/j.tim.2004.09.007. source

      Not checked in the free run.

    • cites [8] 8. Abdallah AM, Gey van Pittius NC, Champion PA, Cox J, Luirink J, Vandenbroucke-Grauls CM, Appelmelk BJ, Bitter W. 2007. Type VII secretion-mycobacteria show the way. Nat Rev Microbiol 5:883-891. http://dx.doi.org/10.1038/nrmicro1773. source

      Not checked in the free run.

    • cites [16] 16. Bitter W, Houben EN, Bottai D, Brodin P, Brown EJ, Cox JS, Derbyshire K, Fortune SM, Gao LY, Liu J, Gey van Pittius NC, Pym AS, Rubin EJ, Sherman DR, Cole ST, Brosch R. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5:e1000507. http://dx.doi.org/10.1371/journal.ppat.1000507. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ESX/T7S systems play an important role in the biology of M. tuberculosis and in its interactions with the host.

    “ESX/T7S systems play an important role in the biology of M. tuberculosis, as well as in the interactions M. tuberculosis has with its host.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The ESX-1 system is involved in bacterial phagosome-to-cytosol transition of M. tuberculosis and host cell death.

    “The ESX-1 system was shown to be involved in bacterial phagosome-tocytosol transition of M. tuberculosis and host cell death (66)(67)(68), an important cell biological process that has numerous consequences for the host cell, such as induc-tion of the cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and NLRP3 inflammasome activation (69)(70)(71)(72)(73)(74)(75).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] 66. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ. 2007. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287- 1298. http://dx.doi.org/10.1016/j.cell.2007.05.059. source

      Not checked in the free run.

    • cites [67] 67. Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, Enninga J. 2012. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog 8:e1002507. http://dx .doi.org/10.1371/journal.ppat.1002507. source

      Not checked in the free run.

    • cites [68] 68. Aguilo JI, Alonso H, Uranga S, Marinova D, Arbués A, de Martino A, Anel A, Monzon M, Badiola J, Pardo J, Brosch R, Martin C. 2013. ESX-1- induced apoptosis is involved in cell-to-cell spread of Mycobacterium tuberculosis. Cell Microbiol 15:1994-2005. http://dx.doi.org/10.1111 /cmi.12169. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    M. canettii strains represent a group of rare tubercle bacilli thought to resemble the ancestor of M. tuberculosis and have been isolated mainly from tuberculosis patients in the Horn of Africa.

    “representing a group of rare tubercle bacilli that are thought to resemble the ancestor of M. tuberculosis and have been isolated mainly from tuberculosis patients in the region of the Horn of Africa (East Africa) (56,57).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] 56. Supply P, Marceau M, Mangenot S, Roche D, Rouanet C, Khanna V, Majlessi L, Criscuolo A, Tap J, Pawlik A, Fiette L, Orgeur M, Fabre M, Parmentier C, Frigui W, Simeone R, Boritsch EC, Debrie AS, Willery E, Walker D, Quail MA, Ma L, Bouchier C, Salvignol G, Sayes F, Cascioferro A, Seemann T, Barbe V, Locht C, Gutierrez MC, Leclerc C, Bentley SD, Stinear TP, Brisse S, Médigue C, Parkhill J, Cruveiller S, Brosch R. 2013. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tubercu- losis. Nat Genet 45:172-179. http://dx.doi.org/10.1038 source

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    • cites [57] 57. Boritsch EC, Frigui W, Cascioferro A, Malaga W, Etienne G, Laval F, Pawlik A, Le Chevalier F, Orgeur M, Ma L, Bouchier C, Stinear TP, Supply P, Majlessi L, Daffé M, Guilhot C, Brosch R. 2016. pks5- recombination-mediated surface remodelling in Mycobacterium tuber- culosis emergence. Nat Microbiol 1:15019. http://dx.doi.org/10.1038 /nmicrobiol.2015.19. source

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    Premisecitation

    ESX-4, ESX-3, and ESX-1 are present in most fast-growing and slow-growing mycobacteria, while ESX-2 and ESX-5 are found only in selected slow-growing mycobacteria and represent the most recently evolved systems.

    “While ESX-4, ESX-3, and ESX-1 are present in most fast-growing and slowgrowing mycobacteria, ESX-2 and ESX-5 systems are found only in selected slow-growing mycobacteria and thus represent the most recently evolved systems (21,22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] 21. Dumas E, Christina Boritsch E, Vandenbogaert M, Rodríguez de la Vega RC, Thiberge JM, Caro V, Gaillard JL, Heym B, Girard-Misguich F, Brosch R, Sapriel G. 2016. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Genome Biol Evol 8:387-402. http://dx.doi.org/10.1093/gbe/evw001. source

      Not checked in the free run.

    • cites [22] 22. Newton-Foot M, Warren RM, Sampson SL, van Helden PD, Gey van Pittius NC. 2016. The plasmid-mediated evolution of the mycobacterial ESX (type VII) secretion systems. BMC Evol Biol 16:62. http://dx.doi.org /10.1186/s12862-016-0631-2. source

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    Premisecitation

    The ESX-5 nanomachine is integrated in the inner mycobacterial membrane and is composed of four proteins, EccB5, EccC5, EccD5, and EccE5, organized in a hexameric complex, as determined by cryo-electron microscopy and single-particle analysis.

    “The ESX-5 nanomachine, which is integrated in the inner mycobacterial membrane, is composed of four proteins, namely, EccB5, EccC5, EccD5, and EccE5 (9, 10), that are organized in a hexameric complex, as recently determined by cryoelectron microscopy and single-particle analysis (10).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. Houben EN, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, Ottenhoff TH, Luirink J, Bitter W. 2012. Composition of the type VII secretion system membrane complex. Mol Microbiol 86:472-484. http:// dx.doi.org/10.1111/j.1365-2958.2012.08206.x. source

      Not checked in the free run.

    • cites [10] 10. Beckham KS, Ciccarelli L, Bunduc CM, Mertens HD, Ummels R, Lugmayr W, Mayr J, Rettel M, Savitski MM, Svergun DI, Bitter W, Wilmanns M, Marlovits TC, Parret AH, Houben EN. 2017. Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis. Nat Microbiol 2:17047. http://dx.doi.org/10 .1038/nmicrobiol.2017.47. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Besides chaperone activity, these proteins are also involved in determining the secretion system specificity.

    “It was suggested that besides their chaperone activity, these proteins are also involved in determining the secretion system specificity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] 49. Phan TH, Ummels R, Bitter W, Houben EN. 2017. Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems. Sci Rep 7:42704. http://dx.doi.org/10.1038/srep42704. source

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    Premisecitation

    Five ESX systems are encoded in the genome of M. tuberculosis, and this is the highest number found in mycobacteria so far; other mycobacterial species show fewer systems (e.g., M. marinum four, M. abscessus three).

    “Five ESX systems are encoded in the genome of M. tuberculosis (16,18), and this number is the highest found in mycobacteria so far; other mycobacterial species show fewer systems (e.g., Mycobacterium marinum shows four systems and Mycobacterium abscessus shows three systems) (21,22).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] 16. Bitter W, Houben EN, Bottai D, Brodin P, Brown EJ, Cox JS, Derbyshire K, Fortune SM, Gao LY, Liu J, Gey van Pittius NC, Pym AS, Rubin EJ, Sherman DR, Cole ST, Brosch R. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5:e1000507. http://dx.doi.org/10.1371/journal.ppat.1000507. source

      Not checked in the free run.

    • cites [18] 18. Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST. 1999. Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber Lung Dis 79:329-342. http://dx.doi.org/10.1054/tuld.1999.0220. source

      Not checked in the free run.

    • cites [21] 21. Dumas E, Christina Boritsch E, Vandenbogaert M, Rodríguez de la Vega RC, Thiberge JM, Caro V, Gaillard JL, Heym B, Girard-Misguich F, Brosch R, Sapriel G. 2016. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Genome Biol Evol 8:387-402. http://dx.doi.org/10.1093/gbe/evw001. source

      Not checked in the free run.

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    Premisecitation

    Among the Ecc proteins, the structural and functional roles of EccC (FtsK/SpoIIIE ATPase) have been studied in more detail with the thermophilic actinobacterium Thermomonospora curvata.

    “Among the Ecc proteins (ESX conserved components), the structural and functional roles of EccC (FtsK/SpoIIIE ATPase) have been studied in more detail with the thermophilic actinobacterium Thermomonospora curvata (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Rosenberg OS, Dovala D, Li X, Connolly L, Bendebury A, Finer- Moore J, Holton J, Cheng Y, Stroud RM, Cox JS. 2015. Substrates control multimerization and activation of the multi-domain ATPase motor of type VII secretion. Cell 161:501-512. http://dx.doi.org/10.1016/j.cell.2015 .03.040. source

      Not checked in the free run.

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    Premisecitation

    SigM, an extracytoplasmic function σ factor, is an activator of ESX-4 expression and necessary for DCT in the recipient strain of M. smegmatis.

    “Moreover, it was shown that SigM, an extracytoplasmic function σ factor, is an activator of ESX-4 expression and necessary for DCT in the recipient strain of M. smegmatis (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] 54. Clark RR, Judd J, Lasek-Nesselquist E, Montgomery SA, Hoffmann JG, Derbyshire KM, Gray TA. 2018. Direct cell-cell contact activates SigM to express the ESX-4 secretion system in Mycobacterium smegmatis. Proc Natl Acad Sci U S A 115:E6595-E6603. http://dx.doi.org/10.1073 /pnas.1804227115. source

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    Premisecitation

    Another conserved ESX component is the serine protease MycP, although this protein is not directly integrated in the EccBCDE complex.

    “Another conserved ESX component in mycobacterial ESX systems is the serine protease MycP, although this protein is not directly integrated in the EccBCDE complex (10,(41)(42)(43).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] 10. Beckham KS, Ciccarelli L, Bunduc CM, Mertens HD, Ummels R, Lugmayr W, Mayr J, Rettel M, Savitski MM, Svergun DI, Bitter W, Wilmanns M, Marlovits TC, Parret AH, Houben EN. 2017. Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis. Nat Microbiol 2:17047. http://dx.doi.org/10 .1038/nmicrobiol.2017.47. source

      Not checked in the free run.

    • cites [41] 41. van Winden VJC, Damen MPM, Ummels R, Bitter W, Houben ENG. 2019. Protease domain and transmembrane domain of the type VII secretion mycosin protease determine system-specific functioning in mycobacteria. J Biol Chem 294:4806-4814. http://dx.doi.org/10.1074 /jbc.RA118.007090. source

      Not checked in the free run.

    • cites [42] 42. Bosserman RE, Champion PA. 2017. Esx systems and the mycobac- terial cell envelope: what's the connection? J Bacteriol 199:e00131-17. http://dx.doi.org/10.1128/JB.00131-17. source

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    Premisecitation

    ESX-1, ESX-3, and ESX-5 all contribute to virulence of M. tuberculosis, although exact molecular functions often remain vague; studies with different mycobacterial species may show species-specific differences.

    “In contrast, for ESX-1, ESX-3, and ESX-5, recent research has determined that they all contribute to virulence of M. tuberculosis, although the insights into the exact molecular functions often remain vague; also, because many studies have been undertaken with different mycobacterial species (M.tuberculosis, M. marinum, M. abscessus, and/or Mycobacterium smegmatis), which may show some species-”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] 11. Gröschel MI, Sayes F, Simeone R, Majlessi L, Brosch R. 2016. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat Rev Microbiol 14:677-691. http://dx.doi.org/10.1038/nrmicro.2016.131. source

      Not checked in the free run.

    • cites [26] 26. Majlessi L, Prados-Rosales R, Casadevall A, Brosch R. 2015. Release of mycobacterial antigens. Immunol Rev 264:25-45. http://dx.doi.org/10 .1111/imr.12251. source

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    • cites [27] 27. Ates LS, Houben EN, Bitter W. 2016. Type VII secretion: a highly versatile secretion system. Microbiol Spectr 4:VMBF-0011-2015. 10.1128/microbiolspec.VMBF-0011-2015. source

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    Premisecitation

    ESX-5 was suggested to be crucial for nutrient uptake and for the export of members of the PE and PPE protein families.

    “ESX-5 was suggested to be crucial for nutrient uptake and for the export of members of the PE and PPE protein families (9,32,33).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] 9. Houben EN, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, Ottenhoff TH, Luirink J, Bitter W. 2012. Composition of the type VII secretion system membrane complex. Mol Microbiol 86:472-484. http:// dx.doi.org/10.1111/j.1365-2958.2012.08206.x. source

      Not checked in the free run.

    • cites [32] 32. Bottai D, Di Luca M, Majlessi L, Frigui W, Simeone R, Sayes F, Bitter W, Brennan MJ, Leclerc C, Batoni G, Campa M, Brosch R, Esin S. 2012. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation. Mol Microbiol 83:1195-1209. http://dx.doi.org/10.1111/j .1365-2958.2012.08001.x. source

      Not checked in the free run.

    • cites [33] 33. Ates LS, Ummels R, Commandeur S, van de Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd El Ghany M, Abdel-Haleem AM, Pain A, Jiménez CR, Bitter W, Houben EN. 2015. Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLoS Genet 11:e1005190. http://dx.doi.org/10.1371/journal.pgen.1005190. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Certain ESX/T7S systems may have a dual function.

    “It is also intriguing that certain ESX/T7S systems may have a dual function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    EspL can have a role as a chaperone and is essential for ESX-1-dependent virulence.

    “In addition, it was suggested that EspL can have a role as a chaperone and is essential for ESX-1dependent virulence (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] 50. Sala C, Odermatt NT, Soler-Arnedo P, Gülen MF, von Schultz S, Benjak A, Cole ST. 2018. EspL is essential for virulence and stabilizes EspE, EspF and EspH levels in Mycobacterium tuberculosis. PLoS Pathog 14:e1007491. http://dx.doi.org/10.1371/journal.ppat.1007491. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to M. canettii strains, DNA transfer between M. tuberculosis strains was not observed despite numerous trials, emphasizing the clonal population structure of M. tuberculosis strains.

    “In contrast to M. canettii strains, DNA transfer between M. tuberculosis strains was not observed despite numerous trials (55), emphasizing the clonal population structure of M. tuberculosis strains (58,59).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [55] 55. Boritsch EC, Khanna V, Pawlik A, Honoré N, Navas VH, Ma L, Bouchier C, Seemann T, Supply P, Stinear TP, Brosch R. 2016. Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria. Proc Natl Acad Sci U S A 113:9876- 9881. http://dx.doi.org/10.1073/pnas.1604921113. source

      Not checked in the free run.

    • cites [58] 58. Godfroid M, Dagan T, Kupczok A. 2018. Recombination signal in Mycobacterium tuberculosis stems from reference-guided assemblies and alignment artefacts. Genome Biol Evol 10:1920-1926. http://dx.doi.org /10.1093/gbe/evy143. source

      Not checked in the free run.

    • cites [59] 59. Orgeur M, Brosch R. 2018. Evolution of virulence in the Mycobac- terium tuberculosis complex. Curr Opin Microbiol 41:68-75. http://dx .doi.org/10.1016/j.mib.2017.11.021. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity.

    “ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity (29)(30)(31).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] 29. Serafini A, Boldrin F, Palù G, Manganelli R. 2009. Characterization of a Mycobacterium tuberculosis ESX-3 conditional mutant: essentiality and rescue by iron and zinc. J Bacteriol 191:6340-6344. http://dx.doi.org /10.1128/JB.00756-09. source

      Not checked in the free run.

    • cites [30] 30. Siegrist MS, Steigedal M, Ahmad R, Mehra A, Dragset MS, Schuster BM, Philips JA, Carr SA, Rubin EJ. 2014. Mycobacterial Esx-3 requires multiple components for iron acquisition. mBio 5:e01073-14. http://dx .doi.org/10.1128/mBio.01073-14. source

      Not checked in the free run.

    • cites [31] 31. Tufariello JM, Chapman JR, Kerantzas CA, Wong KW, Vilchèze C, Jones CM, Cole LE, Tinaztepe E, Thompson V, Fenyö D, Niederweis M, Ueberheide B, Philips JA, Jacobs WR, Jr. 2016. Separable roles for My- cobacterium tuberculosis ESX-3 effectors in iron acquisition and viru- lence. Proc Natl Acad Sci U S A 113:E348-E357. http://dx.doi.org/10 .1073/pnas.1523321113. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ESX systems have a strong impact on mycobacterial host-pathogen interaction, although more work is needed to elucidate the various molecular mechanisms by which the effects are generated.

    “It is clear from the few examples mentioned here that ESX systems have a strong impact on mycobacterial host-pathogen interaction, although more work is needed to elucidate the various molecular mechanisms by which the effects are generated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a recent study using an M. abscessus genome-scale Himar mariner transposon library, an intact ESX-4 system was shown to be needed for full virulence in this fast-growing mycobacterium and emerging human pathogen, whereby the ESX-4 function in infection was associated with phagosomal rupture and transition of bacteria to the cytosol of amoebae and human macrophages.

    “In a recent study, by using an M. abscessus genome-scale Himar mariner transposon library, it was shown that an intact ESX-4 system is needed for full virulence in this fast-growing mycobacterium and emerging human pathogen, whereby the ESX-4 function in infection was associated with phagosomal rupture and transition of bacteria to the cytosol of amoebae and human macrophages (83).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] 83. Laencina L, Dubois V, Le Moigne V, Viljoen A, Majlessi L, Pritchard J, Bernut A, Piel L, Roux AL, Gaillard JL, Lombard B, Loew D, Rubin EJ, Brosch R, Kremer L, Herrmann JL, Girard-Misguich F. 2018. Identifica- tion of genes required for Mycobacterium abscessus growth in vivo with a prominent role of the ESX-4 locus. Proc Natl Acad Sci U S A 115:E1002- E1011. http://dx.doi.org/10.1073/pnas.1713195115. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of ESX-1 is one of the main reasons for the attenuation of the BCG vaccine, while ESX-1 effectors are important antigens in immune responses.

    “Loss of ESX-1 is one of the main reasons for the attenuation of the BCG vaccine (65), while ESX-1 effectors are important antigens in immune responses (6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] 65. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. 2002. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Myco- bacterium bovis BCG and Mycobacterium microti. Mol Microbiol 46:709-717. http://dx.doi.org/10.1046/j.1365-2958.2002.03237.x. source

      Not checked in the free run.

    • cites [6] 6. Sørensen AL, Nagai S, Houen G, Andersen P, Andersen AB. 1995. Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect Immun 63:1710-1717. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Because of extensive sequence similarities and immune cross-reactions among Esx and PE/PPE proteins secreted by the ESX/T7S systems, investigation of the secretion and regulation of these effectors is challenging.

    “Because of extensive sequence similarities and immune cross-reactions among Esx and PE/PPE proteins secreted by the ESX/T7S systems, investigation of the secretion and regulation of these effectors is challenging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Strains of different phylogenetic lineages showed distinct secretion levels of Ag85B proteins in a preliminary set of M. tuberculosis strains by the MASSTT assay, information that needs to be confirmed with a larger strain collection.

    “Interestingly, strains of different phylogenetic lineages showed distinct secretion levels of Ag85B proteins in a preliminary set of M. tuberculosis strains by the MASSTT assay (84), information that needs to be confirmed with a larger strain collection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] 84. Sayes F, Blanc C, Ates LS, Deboosere N, Orgeur M, Le Chevalier F, Gröschel MI, Frigui W, Song OR, Lo-Man R, Brossier F, Sougakoff W, Bottai D, Brodin P, Charneau P, Brosch R, Majlessi L. 2018. Multi- plexed quantitation of intraphagocyte Mycobacterium tuberculosis se- creted protein effectors. Cell Rep 23:1072-1084. http://dx.doi.org/10 .1016/j.celrep.2018.03.125. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ESX-4 loci usually lack pe/ppe and espG genes, which may be involved in host-pathogen interactions, as well as the eccE gene.

    “The ESX-4 loci usually lack pe/ppe and espG genes, which may be involved in host-pathogen interactions (34), as well as the eccE gene.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] 34. Gey van Pittius NC, Sampson SL, Lee H, Kim Y, van Helden PD, Warren RM. 2006. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol Biol 6:95. http://dx.doi.org/10.1186/1471-2148-6-95.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    As M. abscessus does not possess an ESX-1 system, in this particular case, ESX-4 might be considered a surrogate of ESX-1.

    “As M. abscessus does not possess an ESX-1 system, in this particular case, ESX-4 might be considered a surrogate of ESX-1.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: M. abscessus does not possess an ESX-1 system.

  • May combine two claims.

    Premisecitation

    In an ESX-1-dependent manner, the ESCRT machinery is recruited to phagosomes, while ESX-3 effectors (EsxG-EsxH) antagonize the host damage response by blocking the recruitment of HRS, ESCRT-III, and GAL3.

    “In an ESX-1-dependent manner, the ESCRT machinery is recruited to phagosomes, while ESX-3 effectors (EsxG-EsxH) antagonize the host damage response by blocking the recruitment of HRS, ESCRT-III, and GAL3 (81) (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] 81. Mittal E, Skowyra ML, Uwase G, Tinaztepe E, Mehra A, Köster S, Hanson PI, Philips JA. 2018. Mycobacterium tuberculosis type VII se- cretion system effectors differentially impact the ESCRT endomembrane damage response. mBio 9:01765-18. http://dx.doi.org/10.1128/mBio .01765-18. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Due to the absence of ESX-1, BCG does not gain access to the host cell cytosol and thus lacks the induction of certain immune signaling pathways.

    “Due to the absence of ESX-1, BCG does not gain access to the host cell cytosol and thus lacks the induction of certain immune signaling pathways (74,86).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] 74. Kupz A, Zedler U, Stäber M, Perdomo C, Dorhoi A, Brosch R, Kaufmann SH. 2016. ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo. J Clin Invest 126:2109- 2122. http://dx.doi.org/10.1172/JCI84978. source

      Not checked in the free run.

    • cites [86] 86. Simeone R, Sayes F, Song O, Gröschel MI, Brodin P, Brosch R, Majlessi L. 2015. Cytosolic access of Mycobacterium tuberculosis: critical impact of phagosomal acidification control and demonstration of occur- rence in vivo. PLoS Pathog 11:e1004650. http://dx.doi.org/10.1371 /journal.ppat.1004650. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ESX-4 is one of the least well-characterized ESX systems, although it is considered the most ancestral esx locus in mycobacteria.

    “ESX-4 is one of the least well-characterized ESX systems, although it is considered the most ancestral esx locus in mycobacteria (21,82).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] 21. Dumas E, Christina Boritsch E, Vandenbogaert M, Rodríguez de la Vega RC, Thiberge JM, Caro V, Gaillard JL, Heym B, Girard-Misguich F, Brosch R, Sapriel G. 2016. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Genome Biol Evol 8:387-402. http://dx.doi.org/10.1093/gbe/evw001. source

      Not checked in the free run.

    • cites [82] 82. Houben EN, Korotkov KV, Bitter W. 2014. Take five-type VII se- cretion systems of mycobacteria. Biochim Biophys Acta 1843:1707-1716. http://dx.doi.org/10.1016/j.bbamcr.2013.11.003. source

      Not checked in the free run.

30 of 30

  • The paper relies on this without support.

    M. abscessus does not possess an ESX-1 system.

    “As M. abscessus does not possess an ESX-1 system, in this particular case, ESX-4 might be considered a surrogate of ESX-1.”

  • The paper relies on this without support.

    The ESX-1 system is present in both fast-growing and slow-growing mycobacterial species.

    “For example, the ESX-1 system, which is present in fast-and slow-growing mycobacterial species, is required for distributive conjugal transfer (DCT) of chromosomal DNA from donor into recipient strains of M. smegmatis (51,52).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Type VII (ESX) secretion systems are found in all mycobacteria and are encoded primarily in a large, multi-gene locus, esx.

    “Type VII (ESX) secretion systems are found in all mycobacteria and are encoded, primarily, in a large, multi-gene locus, esx (53–57).”

    From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [54]

    The Introduction identifies ESX systems as type VII secretion systems and describes multiple components encoded in different regions of the mycobacterial chromosome. The section on structural and functional characteristics says several ESX systems occur in most fast- and slow-growing mycobacteria, but it does not establish their presence in all mycobacteria. Nor does the paper describe the systems as encoded primarily in one large esx locus; it discusses distinct ESX loci. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

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Related

Authors
Vaziri, F., & Brosch, R.
Affiliations
Centre National de la Recherche Scientifique (FR)
ORCID
Venue
Microbiology Spectrum
Publisher
American Society for Microbiology
Published
2019-07-19
Volume
7
Issue
4
ISSN
2165-0497 (ISSN-L)
DOI
10.1128/microbiolspec.psib-0029-2019
PMC
PMC10957191
OpenAlex
W2956693446
Cited by
50
References
95
Citations by year
2026: 3 · 2025: 9 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 2
FWCI
0.88
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Microbiology Spectrum (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • European Commission (TBVAC2020, 643381, HORIZON2020)
  • Agence Nationale de la Recherche (10-LABX-62-IBEID, ANR‐10‐LABX‐62‐IBEID, ANR-16-CE15-0003, ANR-10, ANR-16-CE35-0009, ANR-10-LABX-62)
  • Fondation pour la Recherche Médicale (ANR-10-LABX-62-IBEID, DEQ20130326471)
  • Campus France
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
Keywords
ESX secretion system, Mycobacterium tuberculosis, type VII secretion system, protein secretion, twin-arginine translocation, host-pathogen interaction, mycobacterial cell envelope, tuberculosis
MeSH terms
Type VII Secretion Systems, Animals, Antigens, Bacterial, Bacterial Proteins, Humans, Mycobacterium tuberculosis, Tuberculosis, Protein Transport, Virulence Factors, Host-Pathogen Interactions

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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