Cyclic AMP signalling in mycobacteria: Redirecting the conversation with a common currency

Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002, USA.
Cellular Microbiology (Impact Factor: 4.92). 03/2011; 13(3):349-58. DOI: 10.1111/j.1462-5822.2010.01562.x
Source: PubMed


cAMP is an ancient second messenger, and is used by many organisms to regulate a wide range of cellular functions. Mycobacterium tuberculosis complex bacteria are exceptional in that they have genes for at least 15 biochemically distinct adenylyl cyclases, the enzymes that generate cAMP. cAMP-associated gene regulation within tubercle bacilli is required for their virulence, and secretion of cAMP produced by M. tuberculosis bacteria into host macrophages disrupts the host's immune response to infection. In this review, we discuss recent advances in our understanding of the means by which cAMP levels are controlled within mycobacteria, the importance of cAMP to M. tuberculosis during host infection, and the role of cAMP in mycobacterial gene regulation. Understanding the myriad aspects of cAMP signalling in tubercle bacilli will establish new paradigms for cAMP signalling, and may contribute to new approaches for prevention and/or treatment of tuberculosis disease.

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    • "The phagolysosome is an acidic, nutrient poor, and oxidatively hostile environment, and bacteria slow down their metabolism to survive [42]. When M. tuberculosis is phagocyted by macrophages, cAMP increases dramatically, and this cAMP is secreted to the phagolysosome, exerting responses in the host which are involved in pathogenesis [43]. "
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    ABSTRACT: Post-translational modification of proteins is a reversible mechanism of cellular adaptation to changing environmental conditions. In eukaryotes, the physiological relevance of N-ɛ-lysine protein acetylation is well demonstrated. In recent times, important roles in the regulation of metabolic processes in bacteria are being uncovered, adding complexity to cellular regulatory networks. The aim of this mini-review is to sum up the current state-of-the-art in the regulation of bacterial physiology by protein acetylation. Current knowledge on the molecular biology aspects of known bacterial protein acetyltransferases and deacetylases will be summarized. Protein acetylation in Escherichia coli, Salmonella enterica, Bacillus subtilis, Rhodopseudomonas palustris and Mycobacterium tuberculosis, will be explained in the light of their physiological relevance. Progress in the elucidation of bacterial acetylomes and the emerging understanding of chemical acylation mechanisms will be discussed together with their regulatory and evolutionary implications. Fundamental molecular studies detailing this recently discovered regulatory mechanism pave the way for their prospective application for the construction of synthetic regulation networks.
    New Biotechnology 12/2014; 31(6). DOI:10.1016/j.nbt.2014.03.002 · 2.90 Impact Factor
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    • "Analysis of the M. tuberculosis H37Rv genome has identified 15 genes and one pseudogene that encode for proteins with predicted AC domains (Shenoy and Visweswariah 2006). Many of the AC present in M. tuberculosis have been biochemically characterized and reviews regarding them have been recently published (Shenoy et al. 2004; Barba et al. 2010; Bai et al. 2011). Despite this characterization, only few of the AC have been associated with the physiology of the slow-growing mycobacteria to date. "
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    ABSTRACT: All organisms have the capacity to sense and respond to environmental changes. These signals often involve the use of second messengers such as cyclic adenosine monophosphate (cAMP). This second messenger is widely distributed among organisms and coordinates gene expression related with pathogenesis, virulence, and environmental adaptation. Genomic analysis in Mycobacterium tuberculosis has identified 16 adenylyl cyclases (AC) and one phosphodiesterase, which produce and degrade cAMP, respectively. To date, ten AC have been biochemically characterized and only one (Rv0386) has been found to be important during murine infection with M. tuberculosis. Here, we investigated the impact of hsp60-driven Rv2212 gene expression in Mycobacterium bovis Bacillus Calmette-Guerin (BCG) during growth in vitro, and during macrophage and mice infection. We found that hsp60-driven expression of Rv2212 resulted in an increased capacity of replication in murine macrophages but an attenuated phenotype in lungs and spleen when administered intravenously in mice. Furthermore, this strain displayed an altered proteome mainly affecting proteins associated with stress conditions (bfrB, groEL-2, DnaK) that could contribute to the attenuated phenotype observed in mice.
    Folia Microbiologica 07/2014; 60(1). DOI:10.1007/s12223-014-0335-1 · 1.00 Impact Factor
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    • "Cellular concentration of cAMP can be regulated at the level of expression and/or activity of AC and the PDE, or by a change in the rate of cAMP export [6], [32]–[34]. Although intracellular cAMP levels are significantly altered in Mtb, we observed that the extracellular cAMP pool remains constant over eight days of in vitro growth (data not shown). "
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    ABSTRACT: Mycobacterium tuberculosis (Mtb) secretes excess of a second messenger molecule, 3',5'-cyclic AMP (cAMP), which plays a critical role in the survival of Mtb in host macrophages. Although Mtb produces cAMP in abundance, its exact role in the physiology of mycobacteria is elusive. In this study we have analyzed the expression of 16 adenylate cyclases (ACs) and kinetics of intracellular cAMP levels in Mtb during in vitro growth under the regular culture conditions, and after exposure to different stress agents. We observed a distinct expression pattern of these ACs which is correlated with intracellular cAMP levels. Interestingly cAMP levels are significantly elevated in Mtb following heat stress, whereas other stress conditions such as oxidative, nitrosative or low pH do not affect intracellular cAMP pool in vitro. A significant increase in expression by >2-fold of five ACs namely Rv1647, Rv2212, Rv1625c, Rv2488c and Rv0386 after heat stress further suggested that cAMP plays an important role in controlling Mtb response to heat stress. In the light of these observations, effect of exogenous cAMP on global gene expression profile was examined by using microarrays. The microarray gene expression analysis demonstrated that cAMP regulates expression of a subset of heat stress-induced genes comprising of dnaK, grpE, dnaJ, and Rv2025c. Further we performed electrophoretic mobility shift assay by using cAMP-receptor protein of Mtb (CRP(M)), which demonstrated that CRP(M) specifically recognizes a sequence -301AGCGACCGTCAGCACG-286 in 5'-untranslated region of dnaK.
    PLoS ONE 02/2014; 9(2):e89759. DOI:10.1371/journal.pone.0089759 · 3.23 Impact Factor
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