Characterization of a Mycobacterium tuberculosis ESX-3 Conditional Mutant: Essentiality and Rescue by Iron and Zinc
Open accessAbstract
Recently, a novel type of secretory pathway, type VII secretion systems (T7SSs), has been characterized in mycobacteria. The chromosomes of Mycobacterium tuberculosis and Mycobacterium bovis encode five T7SSs (ESX-1 to ESX-5). The best characterized of them, ESX-1, is involved in host-pathogen interactions, and its deletion is one of the main causes of M. bovis BCG attenuation. Another T7SS, ESX-3, has been previously shown to be transcriptionally controlled by the zinc uptake repressor (Zur) and by the iron-dependent transcriptional repressor (IdeR), suggesting that it might be involved in zinc and iron homeostasis. In this study, we characterized an M. tuberculosis conditional mutant in which transcription of the ESX-3 gene cluster can be downregulated by anhydrotetracycline. We showed that this T7SS is essential for growth and that this phenotype can be complemented by zinc, iron, or supernatant from a wild-type parental strain culture, demonstrating that the ESX-3 secretion system is responsible for the secretion of some soluble factor(s) required for growth that is probably involved in optimal iron and zinc uptake.
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ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity.
“ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity (29)(30)(31).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [29]
Cites
Genes required for mycobacterial growth defined by high density mutagenesis
Sassetti, C. M., Boyd, D. H., & Rubin, E. J. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03425.x · Cited by 2,544 · see citing works
The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection
Davis, J. M., & Ramakrishnan, L. (2009) · Cell · doi:10.1016/j.cell.2008.11.014 · Cited by 907 · see citing works
Type VII secretion — mycobacteria show the way
Abdallah, A. M., Gey van Pittius, N. C., DiGiuseppe Champion, P. A., Cox, J., Luirink, J., Vandenbroucke-Grauls, C. M. J. E., Appelmelk, B. J., & Bitter, W. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1773 · Cited by 763 · see citing works
Pym, A. S., Brodin, P., Brosch, R., Huerre, M., & Cole, S. T. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.03237.x · Cited by 729 · see citing works
Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis
Pym, A. S., Brodin, P., Majlessi, L., Brosch, R., Demangel, C., Williams, A., Griffiths, K. E., Marchal, G., Leclerc, C., & Cole, S. T. (2003) · Nature Medicine · doi:10.1038/nm859 · Cited by 644 · see citing works
De Voss, J. J., Rutter, K., Schroeder, B. G., Su, H., Zhu, Y., & Barry, C. E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.3.1252 · Cited by 532 · see citing works
Rodríguez, G. M., Voskuil, M. I., Gold, B., Schoolnik, G. K., & Smith, I. (2002) · Infection and Immunity · doi:10.1128/iai.70.7.3371-3381.2002 · Cited by 491 · see citing works
[25] Genetic systems for mycobacteria
Jacobs, W. R., Kalpana, G. V., Cirillo, J. D., Pascopella, L., Snapper, S. B., Udani, R., Jones, W., Barletta, R. G., & Bloom, B. R. (1991) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(91)04027-l · Cited by 430 · see citing works
van Pittius, N. C. G., Sampson, S. L., Lee, H., Kim, Y., van Helden, P. D., & Warren, R. M. (2006) · BMC Evolutionary Biology · doi:10.1186/1471-2148-6-95 · Cited by 423 · see citing works
Gao, L., Guo, S., McLaughlin, B., Morisaki, H., Engel, J. N., & Brown, E. J. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04261.x · Cited by 395 · see citing works
Controlling gene expression in mycobacteria with anhydrotetracycline and Tet repressor
Ehrt, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni013 · Cited by 383 · see citing works
de Jonge, M. I., Pehau‐Arnaudet, G., Fretz, M. M., Félix, R., Bottai, D., Brodin, P. M., Honoré, N., Marchal, G., Jiskoot, W., England, P., et al. (2007) · Journal of Bacteriology · doi:10.1128/jb.00469-07 · Cited by 316 · see citing works
Brodin, P. M., Majlessi, L., Marsollier, L., de Jonge, M. I., Bottai, D., Demangel, C., Hinds, J., Neyrolles, O., Butcher, P. D., Leclerc, C., et al. (2005) · Infection and Immunity · doi:10.1128/iai.74.1.88-98.2006 · Cited by 312 · see citing works
Abdallah, A. M., Verboom, T., Weerdenburg, E. M., van Pittius, N. C. G., Mahasha, P. W., Jiménez, C. R., Parra, M., Cadieux, N., Brennan, M. J., Appelmelk, B. J., et al. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06783.x · Cited by 268 · see citing works
Global Analysis of theMycobacterium tuberculosisZur (FurB) Regulon
Maciag, A. E., Dainese, E., Rodríguez, G. M., Milano, A., Provvedi, R., Pasca, M. R., Smith, I., Palù, G., Riccardi, G., & Manganelli, R. (2006) · Journal of Bacteriology · doi:10.1128/jb.01190-06 · Cited by 257 · see citing works
Self-citationRodríguez, G. M., & Smith, I. (2005) · Journal of Bacteriology · doi:10.1128/jb.188.2.424-430.2006 · Cited by 257 · see citing works
A specific secretion system mediates PPE41 transport in pathogenic mycobacteria
Abdallah, A. M., Verboom, T., Hannes, F., Safi, M., Strong, M., Eisenberg, D. S., Musters, R. J. P., Vandenbroucke‐Grauls, C. M. J. E., Appelmelk, B. J., Luirink, J., et al. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05409.x · Cited by 234 · see citing works
Infection by Tubercular Mycobacteria Is Spread by Nonlytic Ejection from Their Amoeba Hosts
Hagedorn, M., Rohde, K. H., Russell, D. G., & Soldati, T. (2009) · Science · doi:10.1126/science.1169381 · Cited by 222 · see citing works
The ESAT-6/CFP-10 secretion system of Mycobacterium marinum modulates phagosome maturation
Tan, T., Lee, W. L., Alexander, D. C., Grinstein, S., & Liu, J. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00721.x · Cited by 172 · see citing works
The Mycobacterial Cell Envelope
(2008) · ASM Press eBooks · doi:10.1128/9781555815783 · Cited by 170 · see citing works
Mechanisms of iron regulation in mycobacteria: role in physiology and virulence
Rodriguez, G. M., & Smith, I. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03384.x · Cited by 162 · see citing works
The ESX-5 Secretion System of Mycobacterium marinum Modulates the Macrophage Response
Abdallah, A. M., Savage, N. D. L., van Zon, M., Wilson, L., Vandenbroucke‐Grauls, C. M. J. E., van der Wel, N. N., Ottenhoff, T. H. M., & Bitter, W. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.7166 · Cited by 137 · see citing works
Coros, A., Callahan, B., Battaglioli, E., & Derbyshire, K. M. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06299.x · Cited by 137 · see citing works
A new twist on an old pathway – accessory secretion systems
Rigel, N. W., & Braunstein, M. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06294.x · Cited by 126 · see citing works
Cascioferro, A., Delogu, G., Colone, M., Sali, M., Stringaro, A., Arancia, G., Fadda, G., Palù, G., & Manganelli, R. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2007.06023.x · Cited by 120 · see citing works
Self-citationBottai, D., & Brosch, R. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06784.x · Cited by 88 · see citing works
A Transcriptional Regulator of a Pristinamycin Resistance Gene in Streptomyces coelicolor
Folcher, M., Morris, R. P., Dale, G. E., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007690200 · Cited by 64 · see citing works
Transcriptional analysis of ESAT-6 cluster 3 in Mycobacterium smegmatis
Maciag, A. E., Piazza, A., Riccardi, G., & Milano, A. (2009) · BMC Microbiology · doi:10.1186/1471-2180-9-48 · Cited by 34 · see citing works
Quadri, L. E. N. (2014) · ASM Press eBooks · doi:10.1128/9781555815783.ch10 · Cited by 9 · see citing works
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Nutritional immunity beyond iron: a role for manganese and zinc
Kehl-Fie, T. E., & Skaar, E. P. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2009.11.008 · Cited by 634 · see citing works
ESX secretion systems: mycobacterial evolution to counter host immunity
Gröschel, M. I., Sayes, F., Simeone, R., Majlessi, L., & Brosch, R. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.131 · Cited by 382 · see citing works
Take five — Type VII secretion systems of Mycobacteria
Houben, E. N. G., Korotkov, K. V., & Bitter, W. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.11.003 · Cited by 223 · see citing works
Tufariello, J. M., Chapman, J. R., Kerantzas, C. A., Wong, K.-W., Vilchèze, C., Jones, C. M., Cole, L. E., Tinaztepe, E., Thompson, V., Fenyö, D., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523321113 · Cited by 215 · see citing works
Type VI Secretion System Transports Zn2+ to Combat Multiple Stresses and Host Immunity
Wang, T., Si, M., Song, Y., Zhu, W., Gao, F., Wang, Y., Zhang, L., Zhang, W., Wei, G., Luo, Z.-Q., et al. (2015) · PLOS Pathogens · doi:10.1371/journal.ppat.1005020 · Cited by 210 · see citing works
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking
Mehra, A., Zahra, A., Thompson, V., Sirisaengtaksin, N., Wells, A., Porto, M., Köster, S., Penberthy, K., Kubota, Y., Dricot, A., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003734 · Cited by 192 · see citing works
Ates, L. S., Ummels, R., Commandeur, S., van der Weerd, R., Sparrius, M., Weerdenburg, E., Alber, M., Kalscheuer, R., Piersma, S. R., Abdallah, A. M., et al. (2015) · PLOS Genetics · doi:10.1371/journal.pgen.1005190 · Cited by 185 · see citing works
Shiloh, M. U., & DiGiuseppe Champion, P. A. (2010) · Current Opinion in Microbiology · doi:10.1016/j.mib.2009.11.006 · Cited by 137 · see citing works
The ESX-3 Secretion System Is Necessary for Iron and Zinc Homeostasis in Mycobacterium tuberculosis
Serafini, A., Pisu, D., Palù, G., Rodriguez, G. M., & Manganelli, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078351 · Cited by 131 · see citing works
Self-citationSelf-poisoning of <i>Mycobacterium tuberculosis</i> by interrupting siderophore recycling
Jones, C. M., Wells, R. M., Madduri, A. V. R., Renfrow, M. B., Ratledge, C., Moody, D. B., & Niederweis, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311402111 · Cited by 125 · see citing works
Mittal, E., Skowyra, M. L., Uwase, G., Tinaztepe, E., Mehra, A., Köster, S., Hanson, P. I., & Philips, J. A. (2018) · mBio · doi:10.1128/mbio.01765-18 · Cited by 110 · see citing works
Dumas, E., Christina Boritsch, E., Vandenbogaert, M., Rodríguez de la Vega, R. C., Thiberge, J.-M., Caro, V., Gaillard, J.-L., Heym, B., Girard-Misguich, F., Brosch, R., et al. (2016) · Genome Biology and Evolution · doi:10.1093/gbe/evw001 · Cited by 112 · see citing works
Type VII Secretion: A Highly Versatile Secretion System
Ates, L. S., Houben, E. N. G., & Bitter, W. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.vmbf-0011-2015 · Cited by 100 · see citing works
Release of mycobacterial antigens
Majlessi, L., Prados‐Rosales, R., Casadevall, A., & Brosch, R. (2015) · Immunological Reviews · doi:10.1111/imr.12251 · Cited by 93 · see citing works
Tubercle bacilli rely on a type VII army for pathogenicity
Stoop, E. J. M., Bitter, W., & van der Sar, A. M. (2012) · Trends in Microbiology · doi:10.1016/j.tim.2012.07.001 · Cited by 90 · see citing works
Mycobacterial Esx-3 Requires Multiple Components for Iron Acquisition
Siegrist, M. S., Steigedal, M., Ahmad, R., Mehra, A., Dragset, M. S., Schuster, B. M., Philips, J. A., Carr, S. A., & Rubin, E. J. (2014) · mBio · doi:10.1128/mbio.01073-14 · Cited by 87 · see citing works
The plasmid-mediated evolution of the mycobacterial ESX (Type VII) secretion systems
Newton-Foot, M., Warren, R. M., Sampson, S. L., van Helden, P. D., & Gey van Pittius, N. C. (2016) · BMC Evolutionary Biology · doi:10.1186/s12862-016-0631-2 · Cited by 75 · see citing works
Toxin secretion and trafficking by Mycobacterium tuberculosis
Pajuelo, D., Tak, U., Zhang, L., Danilchanka, O., Tischler, A. D., & Niederweis, M. (2021) · Nature Communications · doi:10.1038/s41467-021-26925-1 · Cited by 63 · see citing works
Meddling with metal sensors: Fur-Family proteins as signaling hubs
Steingard, C. H., & Helmann, J. D. (2023) · Journal of Bacteriology · doi:10.1128/jb.00022-23 · Cited by 59 · see citing works
Iron acquisition, assimilation and regulation in mycobacteria
Banerjee, S., Farhana, A., Ehtesham, N. Z., & Hasnain, S. E. (2011) · Infection, Genetics and Evolution · doi:10.1016/j.meegid.2011.02.016 · Cited by 57 · see citing works
ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins
Vaziri, F., & Brosch, R. (2019) · Microbiology Spectrum · doi:10.1128/microbiolspec.psib-0029-2019 · Cited by 50 · see citing works
Structure and Function of the Mycobacterial Type VII Secretion Systems
Bunduc, C. M., Bitter, W., & Houben, E. N. G. (2020) · Annual Review of Microbiology · doi:10.1146/annurev-micro-012420-081657 · Cited by 50 · see citing works
Dragset, M. S., Ioerger, T. R., Zhang, Y. J., Mærk, M., Ginbot, Z., Sacchettini, J. C., Flo, T. H., Rubin, E. J., & Steigedal, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-47905-y · Cited by 49 · see citing works
Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?
Bosserman, R. E., & Champion, P. A. (2017) · Journal of Bacteriology · doi:10.1128/jb.00131-17 · Cited by 42 · see citing works
Lagune, M., Petit, C., Sotomayor, F. V., Johansen, M. D., Beckham, K. S. H., Ritter, C., Girard-Misguich, F., Wilmanns, M., Kremer, L., Maurer, F. P., et al. (2021) · Microbiology · doi:10.1099/mic.0.001054 · Cited by 27 · see citing works
van Winden, V. J. C., Damen, M. P. M., Ummels, R., Bitter, W., & Houben, E. N. G. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007090 · Cited by 15 · see citing works
Mycosins of the Mycobacterial Type VII ESX Secretion System: the Glue That Holds the Party Together
Chen, J. M. (2016) · mBio · doi:10.1128/mbio.02062-16 · Cited by 10 · see citing works
- Authors
- Serafini, A., Boldrin, F., Palù, G., & Manganelli, R.
- Affiliations
- University of Padua (IT)
- Department of Histology, Microbiology, and Medical Biotechnologies, University of Padua, Padua, Italy
- Venue
- Journal of Bacteriology
- Publisher
- American Society for Microbiology
- Published
- 2009-10-15
- Volume
- 191
- Issue
- 20
- Pages
- 6340-6344
- ISSN
- 0021-9193 (ISSN-L)
- 1098-5530
- PMC
- PMC2753049
- OpenAlex
- W1974305305
- Cited by
- 198
- References
- 29
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 5 · 2023: 12 · 2022: 11 · 2021: 11 · 2020: 6 · 2019: 14 · 2018: 9 · 2017: 16 · 2016: 20 · 2015: 20 · 2014: 15 · 2013: 18 · 2012: 8
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Bacteriology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Keywords
- Mycobacterium tuberculosis, type VII secretion system, conditional mutants, anhydrotetracycline, zinc, iron, gene essentiality, soluble factors
- MeSH terms
- Bacterial Proteins, Iron, Mutation, Mycobacterium tuberculosis, Time Factors, Zinc, Culture Media, Conditioned
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