Mutually dependent secretion of proteins required for mycobacterial virulence.
Open accessAbstract
The ESX-1 locus is a region critical for full virulence in Mycobacterium tuberculosis , which encodes two secreted proteins as well as other genes involved in their secretion. The mechanism of secretion of the two proteins, ESAT-6 and CFP-10, and their function remain unknown. Using proteomic methods to search for additional proteins secreted by the ESX-1 locus, we discovered that a protein encoded by a chromosomally unlinked gene, espA , is also secreted by strains that contain the ESX-1 locus but not by strains with ESX-1 deletions. Mutations in individual ESX-1 genes, including those that encode ESAT-6 and CFP-10, were found to block EspA secretion. Surprisingly, mutants that lack espA reciprocally failed to secrete ESAT-6 and CFP-10 and were as attenuated as ESX-1 mutants in virulence assays. The results indicate that secretion of these proteins, which are each critical for virulence of pathogenic mycobacteria, is mutually dependent. The results further suggest that discerning the nature of the interaction and the structure of macromolecular complexes will provide insights into both an alternative mechanism of protein secretion and mycobacterial virulence.
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Four ESX-1 substrates have been identified in addition to ESAT-6 and CFP-10: EspA, EspB, EspR, and the M. marinum homologue of Rv3864.
“Thus far, four ESX-1 substrates have been identified in addition to ESAT-6 and CFP-10. These substrates are called EspA [39], EspB [46], EspR [41], and the M. marinum homologue of Rv3864 [22].”
From Systematic Genetic Nomenclature for Type VII Secretion Systems (2009) · cites this paper as [39]
Different proteins, such as EspA, EspC, EspD, and EccA1, may be essential to contributing to secretion and stabilizing the core ESX/T7S complex in the case of ESX-1.
“Moreover, different proteins, such as EspA, EspC, EspD, and EccA1, may be essential to contributing to secretion and stabilizing the core ESX/T7S complex in the case of ESX-1 (44)(45)(46)(47).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [44]
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- Authors
- Fortune, S. M., Jaeger, A., Sarracino, D. A., Chase, M. R., Sassetti, C. M., Sherman, D. R., Bloom, B. R., & Rubin, E. J.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-07-19
- Volume
- 102
- Issue
- 30
- Pages
- 10676-10681
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1176248
- OpenAlex
- W2143061508
- Cited by
- 396
- References
- 25
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 14 · 2023: 11 · 2022: 12 · 2021: 20 · 2020: 22 · 2019: 22 · 2018: 15 · 2017: 17 · 2016: 17 · 2015: 18 · 2014: 31 · 2013: 21 · 2012: 24
- FWCI
- 14.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL64550, R01HL068533, R01HL064550, HL68533)
- National Institute of Allergy and Infectious Diseases (AI 48704, AI-07118, R01AI007118, AI50734, R01AI023545, AI23545, R01AI048704, R01AI051929, AI51929, K08AI050734)
- 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, ESAT-6, CFP-10, EspA, protein secretion, virulence factors, secretory pathway, virulence attenuation, protein secretion mechanism
- MeSH terms
- Animals, Antigens, Bacterial, Bacterial Proteins, Base Sequence, Genetic Vectors, Molecular Sequence Data, Mycobacterium tuberculosis, Mass Spectrometry, Tuberculosis, Virulence, Blotting, Western, Mice, SCID, Proteomics, Multiprotein Complexes, Mice
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