TY - JOUR
T1 - Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates
AU - Wang, Lin
AU - Asare, Emmanuel
AU - Shetty, Amol C.
AU - Sanchez-Tumbaco, Freddy
AU - Edwards, Megan R.
AU - Saranathan, Rajagopalan
AU - Weinrick, Brian
AU - Xu, Jiayong
AU - Chen, Bing
AU - Bénard, Angèle
AU - Dougan, Gordon
AU - Leung, Daisy W.
AU - Amarasinghe, Gaya K.
AU - Chan, John
AU - Basler, Christopher F.
AU - Jacobs, William R.
AU - Tufariello, Jo Ann M.
N1 - Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/2/22
Y1 - 2022/2/22
N2 - 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.
AB - 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.
KW - ESX-3
KW - TetR-family transcriptional regulator
KW - genetic accordion
KW - mycobacterium tuberculosis
KW - type VII secretion system
UR - http://www.scopus.com/inward/record.url?scp=85125156060&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125156060&partnerID=8YFLogxK
U2 - 10.1073/pnas.2112608119
DO - 10.1073/pnas.2112608119
M3 - Article
C2 - 35193958
AN - SCOPUS:85125156060
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
M1 - e2112608119
ER -
