Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria
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Type
ArticleAuthors
Ates, Louis S.
Ummels, Roy
Commandeur, Susanna
van der Weerd, Robert
Sparrius, Marion
Weerdenburg, Eveline
Alber, Marina
Kalscheuer, Rainer
Piersma, Sander R.
Abdallah, Abdallah
Abd El Ghany, Moataz
Abdel-Haleem, Alyaa M.

Pain, Arnab

Jiménez, Connie R.
Bitter, Wilbert

Houben, Edith N.G.
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Date
2015-05-04Permanent link to this record
http://hdl.handle.net/10754/552778
Metadata
Show full item recordAbstract
Mycobacteria possess different type VII secretion (T7S) systems to secrete proteins across their unusual cell envelope. One of these systems, ESX-5, is only present in slow-growing mycobacteria and responsible for the secretion of multiple substrates. However, the role of ESX-5 substrates in growth and/or virulence is largely unknown. In this study, we show that esx-5 is essential for growth of both Mycobacterium marinum and Mycobacterium bovis. Remarkably, this essentiality can be rescued by increasing the permeability of the outer membrane, either by altering its lipid composition or by the introduction of the heterologous porin MspA. Mutagenesis of the first nucleotide-binding domain of the membrane ATPase EccC5 prevented both ESX-5-dependent secretion and bacterial growth, but did not affect ESX-5 complex assembly. This suggests that the rescuing effect is not due to pores formed by the ESX-5 membrane complex, but caused by ESX-5 activity. Subsequent proteomic analysis to identify crucial ESX-5 substrates confirmed that all detectable PE and PPE proteins in the cell surface and cell envelope fractions were routed through ESX-5. Additionally, saturated transposon-directed insertion-site sequencing (TraDIS) was applied to both wild-type M. marinum cells and cells expressing mspA to identify genes that are not essential anymore in the presence of MspA. This analysis confirmed the importance of esx-5, but we could not identify essential ESX-5 substrates, indicating that multiple of these substrates are together responsible for the essentiality. Finally, examination of phenotypes on defined carbon sources revealed that an esx-5 mutant is strongly impaired in the uptake and utilization of hydrophobic carbon sources. Based on these data, we propose a model in which the ESX-5 system is responsible for the transport of cell envelope proteins that are required for nutrient uptake. These proteins might in this way compensate for the lack of MspA-like porins in slow-growing mycobacteria.Citation
Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria 2015, 11 (5):e1005190 PLOS GeneticsPublisher
Public Library of Science (PLoS)Journal
PLOS GeneticsPubMed ID
25938982PubMed Central ID
PMC4418733Additional Links
http://dx.plos.org/10.1371/journal.pgen.1005190ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1005190
Scopus Count
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