ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage

Estorninho, Megan; Smith, Hilde E.; Thole, Jelle; Harders-Westerveen, Jose; Kierzek, Andrzej; Butler, Rachel E.; Neyrolles, Olivier; Stewart, Graham R.

doi:10.1099/mic.0.042275-0

Cited by 59 publications

(73 citation statements)

References 48 publications

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“…Rv2745c encodes the ClgR transcription factor, which is an ortholog of the Clp protease gene regulator (23,62). ClgR regulates the expression of its own operon and various other determinants (23), including the ClpC1 and ClpP2 proteases responsible for degradation of the SigE anti-sigma factor, RseA (21). Interestingly, clgR expression is induced by a variety of different stress conditions, including redox stress, cell envelope stress, stress induced following heat shock, and acid stress (62)(63)(64)(65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

“…While the significance of this difference is unclear, the presence of Rv2742c in human TB-causing species indicates that inclusion of this gene may confer additional capabilities to this system that are associated with virulence and/or disease elicitation. Rv2745c encodes the ClgR transcription factor, which is an ortholog of the Clp protease gene regulator (23,62). ClgR regulates the expression of its own operon and various other determinants (23), including the ClpC1 and ClpP2 proteases responsible for degradation of the SigE anti-sigma factor, RseA (21).…”

Section: Discussionmentioning

confidence: 99%

“…However, in addition to this higher level integration, a subset of downstream determinants within each regulon are shared and are directly or indirectly coregulated by MprAB, SigE, and PknB. One such locus is the four-gene operon encoding Rv2745c (ClgR)-Rv2744c-Rv2743c-Rv2742c (20,21,23), which recently was predicted to encode a minimal functional unit of an M. tuberculosis phage shock protein (Psp) system (24).…”

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confidence: 99%

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Rv2744c Is a PspA Ortholog That Regulates Lipid Droplet Homeostasis and Nonreplicating Persistence in Mycobacterium tuberculosis

et al. 2016

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Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant cause of morbidity and mortality worldwide, despite the availability of a live attenuated vaccine and anti-TB antibiotics. The vast majority of individuals infected with M. tuberculosis develop an asymptomatic latent infection in which the bacterium survives within host-generated granulomatous lesions in a physiologically altered metabolic state of nonreplicating persistence. The granuloma represents an adverse environment, as M. tuberculosis is exposed to various stressors capable of disrupting the essential constituents of the bacterium. In Gram-negative and Gram-positive bacteria, resistance to cell envelope stressors that perturb the plasma membrane is mediated in part by proteins comprising the phage shock protein (Psp) system. PspA is an important component of the Psp system; in the presence of envelope stress, PspA localizes to the inner face of the plasma membrane, homo-oligomerizes to form a large scaffold-like complex, and helps maintain plasma membrane integrity to prevent a loss of proton motive force. M. tuberculosis and other members of the Mycobacterium genus are thought to encode a minimal functional unit of the Psp system, including an ortholog of PspA. Here, we show that Rv2744c possesses structural and physical characteristics that are consistent with its designation as a PspA family member. However, although Rv2744c is upregulated under conditions of cell envelope stress, loss of Mycobacterium tuberculosis is the causative agent of the respiratory disease tuberculosis (TB) and is a human-specific pathogen of global importance. This bacterium is responsible for Ͼ9.6 million new cases of TB and 1.5 million deaths annually (1), ranking TB as the leading cause of death in the world due to an infectious agent, alongside HIV/AIDS. A key aspect of the M. tuberculosis life cycle is its ability to establish asymptomatic latent infections and reactivate to cause active disease and transmission to new hosts (reviewed in reference 2). During latency, M. tuberculosis exists in a state of nonreplicating persistence (NRP), a poorly understood physiological state in which the bacterium can utilize alternative carbon sources and energy-generating pathways for long-term survival within the host (3-6). While a live attenuated vaccine for TB is available (Mycobacterium bovis bacillus Calmette-Guérin [BCG]), its efficacy at preventing adult pulmonary TB and thus M. tuberculosis retransmission is highly varied (7,8). Furthermore, M. tuberculosis exhibits increased phenotypic resistance to anti-TB antibiotics during NRP (2, 9), making it more difficult to kill this organism in latently infected individuals. Therefore, new strategies and/or therapeutics are urgently needed to help eradicate TB. This will require an improved understanding of the mechanisms utilized by M. tuberculosis to persist and/or reactivate within the host.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rv2744c Is a PspA Ortholog That Regulates Lipid Droplet Homeostasis and Nonreplicating Persistence in Mycobacterium tuberculosis

et al. 2016

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“…Regulation of ClpP1-ClpP2 expression is mediated by the ClgR regulator (8,9,30); both clpP genes are highly expressed during aerobic and hypoxic growth (24) and are further upregulated during reaeration from anaerobic conditions (30), suggesting a key role in maintaining protein function during changes in oxygen availability. In addition, ClgR-mediated upregulation of Clp genes is required during bacterial infection of macrophages (9).…”

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confidence: 99%

Validation of the Essential ClpP Protease in Mycobacterium tuberculosis as a Novel Drug Target

et al. 2012

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Mycobacterium tuberculosis is a pathogen of major global importance. Validated drug targets are required in order to develop novel therapeutics for drug-resistant strains and to shorten therapy. The Clp protease complexes provide a means for quality control of cellular proteins; the proteolytic activity of ClpP in concert with the ATPase activity of the ClpX/ClpC subunits results in degradation of misfolded or damaged proteins. Thus, the Clp system plays a major role in basic metabolism, as well as in stress responses and pathogenic mechanisms. M. tuberculosis has two ClpP proteolytic subunits. Here we demonstrate that ClpP1 is essential for viability in this organism in culture, since the gene could only be deleted from the chromosome when a second functional copy was provided. Overexpression of clpP1 had no effect on growth in aerobic culture or viability under anaerobic conditions or during nutrient starvation. In contrast, clpP2 overexpression was toxic, suggesting different roles for the two homologs. We synthesized known activators of ClpP protease activity; these acyldepsipeptides (ADEPs) were active against M. tuberculosis. ADEP activity was enhanced by the addition of efflux pump inhibitors, demonstrating that ADEPs gain access to the cell but that export occurs. Taken together, the genetic and chemical validation of ClpP as a drug target leads to new avenues for drug discovery.

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“…Bacteria have evolved accurate regulatory systems to control the expression and function of potentially destructive proteases and chaperones. For example, the Clp Gene Regulator (ClgR) of M.tuberculosis activates the transcription of at least ten genes including four of which encode protease systems (ClpP1/C, ClpP2/C, PrtB and an HtrA-like protease-Rv1043c) and three of which encode chaperones (Acr2, ClpB and Rv3269) [25]. HtrA-like serine protease encoded by pepD, are responsible for degrading or refolding protein substrates following exposure to stress.…”

Section: Tb Proteins Suit For Host Stressmentioning

confidence: 99%

Proteomic progress in studying tuberculosis from 2010 to 2011

Zhang¹,

Lowrie²,

Zhou³

2011

JBPC

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It is well accepted that rapid and early detection of Mycobacterium tuberculosis infection and understanding the mechanism of microbiologyhost interaction. Herein, we review the recently published papers related to TB proteomics from 2010 to 2011, including new technologies used in TB proteome research, diagnosis biomarkers of TB-associated diseases, disease pathogenesis and antigens for drug development. Through this review, we wish to offer some help for TB diagnosis and treatment.

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ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage

Cited by 59 publications

References 48 publications

Rv2744c Is a PspA Ortholog That Regulates Lipid Droplet Homeostasis and Nonreplicating Persistence in Mycobacterium tuberculosis

Rv2744c Is a PspA Ortholog That Regulates Lipid Droplet Homeostasis and Nonreplicating Persistence in Mycobacterium tuberculosis

Validation of the Essential ClpP Protease in Mycobacterium tuberculosis as a Novel Drug Target

Proteomic progress in studying tuberculosis from 2010 to 2011

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