Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 28, Pages 11568-11573Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705054104
Keywords
carbon monoxide; dormancy; nitric oxide; oxygen; persistence
Categories
Funding
- NHLBI NIH HHS [R01 HL074391, HL074391, R01 HL071189, HL71189] Funding Source: Medline
- NIAID NIH HHS [R56 AI058131, AI058131, R01 AI058131] Funding Source: Medline
Ask authors/readers for more resources
A fundamental challenge to the study of oxidative stress responses of Mycobacterium tuberculosis (Mtb) is to understand how the protective host molecules are sensed and relayed to control bacilli gene expression. The genetic response of Mtb to hypoxia and NO is controlled by the sensor kinases DosS and DosT and the response regulator DosR through activation of the dormancy/NO (Dos) regulon. However, the regulatory ligands of DosS and DosT and the mechanism of signal sensing were unknown. Here, we show that both DosS and DosT bind heme as a prosthetic group and that DosS is rapidly autooxiclized to attain the met (Fe3+) form, whereas DosT exists in the O-2-bound (oxy) form. EPR and UV-visible spectroscopy analysis showed that O-2, NO, and CO are ligands of DosS and DosT. Importantly, we demonstrate that the oxidation or ligation state of the heme iron modulates DosS and DosT autokinase activity and that ferrous DosS, and deoxy DosT, show significantly increased autokinase activity compared with met DosS and oxy DosT. Our data provide direct proof that DosS functions as a redox sensor, whereas DosT functions as a hypoxia sensor, and that O-2, NO, and CO are modulatory ligands of DosS and DosT. Finally, we identified a third potential dormancy signal, CO, that induces the Mtb Dos regulon. We conclude that Mtb has evolved finely tuned redox and hypoxia-mediated sensing strategies for detecting O-2, NO, and CO. Data presented here establish a paradigm for understanding the mechanism of bacilli persistence.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available