TY - JOUR
T1 - CarD Is an Essential Regulator of rRNA Transcription Required for Mycobacterium tuberculosis Persistence
AU - Stallings, Christina L.
AU - Stephanou, Nicolas C.
AU - Chu, Linda
AU - Hochschild, Ann
AU - Nickels, Bryce E.
AU - Glickman, Michael S.
N1 - Funding Information:
The authors thank Dirk Schnappinger and Sabine Ehrt for reagents and advice about the tet system, Alex Lash for assistance with bioinformatic analyses, Seth Darst for advice and design of the thermus β fragment, Nigel Savery for materials and assistance relating to the roadblock repression assays, the Genomics Core at MSKCC for microarray hybridization and processing, and Ken Marians for critical reading of the manuscript. M. smegmatis microarrays were provided by NIAID/PFGRC. This work was supported by NIH grant GM073829 to Seth Darst, GM44025 to A.H., AI064693 to M.S.G., and AI075805 to C.L.S.
PY - 2009/7/10
Y1 - 2009/7/10
N2 - Mycobacterium tuberculosis is arguably the world's most successful infectious agent because of its ability to control its own cell growth within the host. Bacterial growth rate is closely coupled to rRNA transcription, which in E. coli is regulated through DksA and (p)ppGpp. The mechanisms of rRNA transcriptional control in mycobacteria, which lack DksA, are undefined. Here we identify CarD as an essential mycobacterial protein that controls rRNA transcription. Loss of CarD is lethal for mycobacteria in culture and during infection of mice. CarD depletion leads to sensitivity to killing by oxidative stress, starvation, and DNA damage, accompanied by failure to reduce rRNA transcription. CarD can functionally replace DksA for stringent control of rRNA transcription, even though CarD associates with a different site on RNA polymerase. These findings highlight a distinct molecular mechanism for regulating rRNA transcription in mycobacteria that is critical for M. tuberculosis pathogenesis.
AB - Mycobacterium tuberculosis is arguably the world's most successful infectious agent because of its ability to control its own cell growth within the host. Bacterial growth rate is closely coupled to rRNA transcription, which in E. coli is regulated through DksA and (p)ppGpp. The mechanisms of rRNA transcriptional control in mycobacteria, which lack DksA, are undefined. Here we identify CarD as an essential mycobacterial protein that controls rRNA transcription. Loss of CarD is lethal for mycobacteria in culture and during infection of mice. CarD depletion leads to sensitivity to killing by oxidative stress, starvation, and DNA damage, accompanied by failure to reduce rRNA transcription. CarD can functionally replace DksA for stringent control of rRNA transcription, even though CarD associates with a different site on RNA polymerase. These findings highlight a distinct molecular mechanism for regulating rRNA transcription in mycobacteria that is critical for M. tuberculosis pathogenesis.
KW - HUMDISEASE
KW - MICROBIO
UR - http://www.scopus.com/inward/record.url?scp=67649660560&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2009.04.041
DO - 10.1016/j.cell.2009.04.041
M3 - Article
C2 - 19596241
AN - SCOPUS:67649660560
VL - 138
SP - 146
EP - 159
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -