ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage.
Chaperone and protease systems play essential roles in cellular homeostasis and have vital functions in controlling the abundance of specific cellular proteins involved in processes such as transcription, replication, metabolism and virulence. Bacteria have evolved accurate regulatory systems to control the expression and function of chaperones and potentially destructive proteases. Here, we have used a combination of transcriptomics, proteomics and targeted mutagenesis to reveal that the clp gene regulator (ClgR) of Mycobacterium tuberculosis activates the transcription of at least ten genes, including four that encode protease systems (ClpP1/C, ClpP2/C, PtrB and HtrA-like protease Rv1043c) and three that encode chaperones (Acr2, ClpB and the chaperonin Rv3269). Thus, M. tuberculosis ClgR controls a larger network of protein homeostatic and regulatory systems than ClgR in any other bacterium studied to date. We demonstrate that ClgR-regulated transcriptional activation of these systems is essential for M. tuberculosis to replicate in macrophages. Furthermore, we observe that this defect is manifest early in infection, as M. tuberculosis lacking ClgR is deficient in the ability to control phagosome pH 1&emsp14;h post-phagocytosis.
Estorninho
Megan
M
Division of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
Smith
Hilde
H
Central Veterinary Institute of Wageningen UR, Division of Infectious Diseases, Animal Sciences Group, Edelhertweg 15, 8219 PH Lelystad, The Netherlands.
Thole
Jelle
J
Central Veterinary Institute of Wageningen UR, Division of Infectious Diseases, Animal Sciences Group, Edelhertweg 15, 8219 PH Lelystad, The Netherlands.
Harders-Westerveen
Jose
J
Central Veterinary Institute of Wageningen UR, Division of Infectious Diseases, Animal Sciences Group, Edelhertweg 15, 8219 PH Lelystad, The Netherlands.
Kierzek
Andrzej
A
Division of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
Butler
Rachel E
RE
Division of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
Neyrolles
Olivier
O
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique and Université Paul Sabatier (UMR 5089), 205 Route de Narbonne, 31000 Toulouse, France.
Stewart
Graham R
GR
Division of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D005809:Genes, Regulator; D005816:Genetic Complementation Test; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics*; D010588:Phagosomes / Q000382:microbiology; D040901:Proteomics; D018085:Regulon; D015533:Transcriptional Activation
D001426:Bacterial Proteins; D018832:Molecular Chaperones; D010447:Peptide Hydrolases