Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates

Lin Wang, Emmanuel Asare, Amol C. Shetty, Freddy Sanchez-Tumbaco, Megan R. Edwards, Rajagopalan Saranathan, Brian Weinrick, Jiayong Xu, Bing Chen, Angèle Bénard, Gordon Dougan, Daisy W. Leung, Gaya K. Amarasinghe, John Chan, Christopher F. Basler, William R. Jacobs, Jo Ann M. Tufariello

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Mycobacterium tuberculosis (Mtb) possesses five type VII secretion systems (T7SS), virulence determinants that include the secretion apparatus and associated secretion substrates. Mtb strains deleted for the genes encoding substrates of the ESX-3 T7SS, esxG or esxH, require iron supplementation for in vitro growth and are highly attenuated in vivo. In a subset of infected mice, suppressor mutants of esxG or esxH deletions were isolated, which enabled growth to high titers or restored virulence. Suppression was conferred by mechanisms that cause overexpression of an ESX-3 paralogous region that lacks genes for the secretion apparatus but encodes EsxR and EsxS, apparent ESX-3 orphan substrates that functionally compensate for the lack of EsxG or EsxH. The mechanisms include the disruption of a transcriptional repressor and a massive 38- to 60-fold gene amplification. These data identify an iron acquisition regulon, provide insight into T7SS, and reveal a mechanism of Mtb chromosome evolution involving “accordion-type” amplification.

Original languageEnglish (US)
Article numbere2112608119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number8
DOIs
StatePublished - Feb 22 2022

Keywords

  • ESX-3
  • TetR-family transcriptional regulator
  • genetic accordion
  • mycobacterium tuberculosis
  • type VII secretion system

ASJC Scopus subject areas

  • General

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