Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence

JoAnn M. Tufariello, Jessica R. Chapman, Christopher A. Kerantzas, Ka Wing Wong, Catherine Vilchèze, Christopher M. Jones, Laura E. Cole, Emir Tinaztepe, Victor Thompson, David Fenyö, Michael Niederweis, Beatrix Ueberheide, Jennifer A. Philips, William R. Jacobs

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems (T7SS), designated ESX-1-ESX-5, that are critical for growth and pathogenesis. The best characterized is ESX-1, which profoundly impacts host cell interactions. In contrast, the ESX-3 T7SS is implicated in metal homeostasis, but efforts to define its function have been limited by an inability to recover deletion mutants. We overcame this impediment using medium supplemented with various iron complexes to recover mutants with deletions encompassing select genes within esx-3 or the entire operon. The esx-3 mutants were defective in uptake of siderophore-bound iron and dramatically accumulated cell-associated mycobactin siderophores. Proteomic analyses of culture filtrate revealed that secretion of EsxG and EsxH was codependent and that EsxG-EsxH also facilitated secretion of several members of the proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) protein families (named for conserved PE and PPE N-terminalmotifs). Substrates that depended on EsxG-EsxH for secretion included PE5, encoded within the esx-3 locus, and the evolutionarily related PE15-PPE20 encoded outside the esx-3 locus. In vivo characterization of the mutants unexpectedly showed that the ESX-3 secretion system plays both irondependent and -independent roles in Mtb pathogenesis. PE5-PPE4 was found to be critical for the siderophore-mediated iron-acquisition functions of ESX-3. The importance of this iron-acquisition function was dependent upon host genotype, suggesting a role for ESX-3 secretion in counteracting host defense mechanisms that restrict iron availability. Further, we demonstrate that the ESX-3 T7SS secretes certain effectors that are important for iron uptake while additional secreted effectors modulate virulence in an iron-independent fashion.

Original languageEnglish (US)
Pages (from-to)E348-E357
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number3
DOIs
StatePublished - Jan 19 2016

Fingerprint

Mycobacterium tuberculosis
Virulence
Proline
Iron
Siderophores
Glutamic Acid
Operon
Cell Communication
Proteomics
Homeostasis
Metals
Genotype
Growth
Genes
Proteins

Keywords

  • ESX-3
  • Mycobacterium tuberculosis
  • Mycobactin
  • Siderophore
  • Type VII secretion system

ASJC Scopus subject areas

  • General

Cite this

Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. / Tufariello, JoAnn M.; Chapman, Jessica R.; Kerantzas, Christopher A.; Wong, Ka Wing; Vilchèze, Catherine; Jones, Christopher M.; Cole, Laura E.; Tinaztepe, Emir; Thompson, Victor; Fenyö, David; Niederweis, Michael; Ueberheide, Beatrix; Philips, Jennifer A.; Jacobs, William R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 3, 19.01.2016, p. E348-E357.

Research output: Contribution to journalArticle

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 2016, 'Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 3, pp. E348-E357. https://doi.org/10.1073/pnas.1523321113
Tufariello, JoAnn M. ; Chapman, Jessica R. ; Kerantzas, Christopher A. ; Wong, Ka Wing ; Vilchèze, Catherine ; Jones, Christopher M. ; Cole, Laura E. ; Tinaztepe, Emir ; Thompson, Victor ; Fenyö, David ; Niederweis, Michael ; Ueberheide, Beatrix ; Philips, Jennifer A. ; Jacobs, William R. / Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 3. pp. E348-E357.
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