Your browser doesn't support javascript.
loading
Mycobacterium tuberculosis SufR responds to nitric oxide via its 4Fe-4S cluster and regulates Fe-S cluster biogenesis for persistence in mice.
Anand, Kushi; Tripathi, Ashutosh; Shukla, Kaustubh; Malhotra, Nitish; Jamithireddy, Anil Kumar; Jha, Rajiv Kumar; Chaudhury, Susmit Narayan; Rajmani, Raju S; Ramesh, Arati; Nagaraja, Valakunja; Gopal, Balasubramanian; Nagaraju, Ganesh; Narain Seshayee, Aswin Sai; Singh, Amit.
Afiliação
  • Anand K; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, 560012, India.
  • Tripathi A; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, 560012, India.
  • Shukla K; Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
  • Malhotra N; National Centre for Biological Science, Bangalore, 560065, India.
  • Jamithireddy AK; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
  • Jha RK; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
  • Chaudhury SN; National Centre for Biological Science, Bangalore, 560065, India.
  • Rajmani RS; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, 560012, India.
  • Ramesh A; National Centre for Biological Science, Bangalore, 560065, India.
  • Nagaraja V; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
  • Gopal B; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
  • Nagaraju G; Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
  • Narain Seshayee AS; National Centre for Biological Science, Bangalore, 560065, India.
  • Singh A; Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, 560012, India; Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India. Electronic address: asingh@iisc.ac.in.
Redox Biol ; 46: 102062, 2021 10.
Article em En | MEDLINE | ID: mdl-34392160
ABSTRACT
The persistence of Mycobacterium tuberculosis (Mtb) is a major problem in managing tuberculosis (TB). Host-generated nitric oxide (NO) is perceived as one of the signals by Mtb to reprogram metabolism and respiration for persistence. However, the mechanisms involved in NO sensing and reorganizing Mtb's physiology are not fully understood. Since NO damages iron-sulfur (Fe-S) clusters of essential enzymes, the mechanism(s) involved in regulating Fe-S cluster biogenesis could help Mtb persist in host tissues. Here, we show that a transcription factor SufR (Rv1460) senses NO via its 4Fe-4S cluster and promotes persistence of Mtb by mobilizing the Fe-S cluster biogenesis system; suf operon (Rv1460-Rv1466). Analysis of anaerobically purified SufR by UV-visible spectroscopy, circular dichroism, and iron-sulfide estimation confirms the presence of a 4Fe-4S cluster. Atmospheric O2 and H2O2 gradually degrade the 4Fe-4S cluster of SufR. Furthermore, electron paramagnetic resonance (EPR) analysis demonstrates that NO directly targets SufR 4Fe-4S cluster by forming a protein-bound dinitrosyl-iron-dithiol complex. DNase I footprinting, gel-shift, and in vitro transcription assays confirm that SufR directly regulates the expression of the suf operon in response to NO. Consistent with this, RNA-sequencing of MtbΔsufR demonstrates deregulation of the suf operon under NO stress. Strikingly, NO inflicted irreversible damage upon Fe-S clusters to exhaust respiratory and redox buffering capacity of MtbΔsufR. Lastly, MtbΔsufR failed to recover from a NO-induced non-growing state and displayed persistence defect inside immune-activated macrophages and murine lungs in a NO-dependent manner. Data suggest that SufR is a sensor of NO that supports persistence by reprogramming Fe-S cluster metabolism and bioenergetics.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Ferro-Enxofre / Mycobacterium tuberculosis Limite: Animals Idioma: En Revista: Redox Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Índia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Ferro-Enxofre / Mycobacterium tuberculosis Limite: Animals Idioma: En Revista: Redox Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Índia