CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence.
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.
Stallings
Christina L
CL
Immunology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Stephanou
Nicolas C
NC
Chu
Linda
L
Hochschild
Ann
A
Nickels
Bryce E
BE
Glickman
Michael S
MS
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D004249:DNA Damage; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D050296:Microbial Viability; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012335:RNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014376:Tuberculosis / Q000382:microbiology*; D015854:Up-Regulation
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D012335:RNA, Ribosomal; D014157:Transcription Factors; C090751:dksA protein, E coli; C072103:transcription repair coupling factor protein, Bacteria