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tuberculosis CDC1551 genome contains seventeen adenylate cyclase ... Cyclic AMP, Mycobacterium tuberculosis, Phosphodiesterase, Signal transduction,.
Indian Journal of Experimental Biology Vol. 47, June 2009, pp. 393-400

Review Article

cAMP signaling in Mycobacterium tuberculosis Nisheeth Agarwal & William R Bishai* Departtment of Medicine, Johns Hopkins School of Medicine, CRB2, Rm 1.08, 1550 Orleans Street, Baltimore, Maryland 21231-1044, USA cAMP is an important second messenger in both eukaryotic and prokaryotic organisms. Several bacterial pathogens have developed mechanisms to subvert eukaryotic cAMP signaling by injecting protein toxins that are themselves adenylate cyclases or by introducing toxins that modify host adenylate cyclases to an overexpression state. Curiously, Mycobacterium tuberculosis CDC1551 genome contains seventeen adenylate cyclase homologues suggesting that cAMP signaling is both relevant and complex in biology of M. tuberculosis. The present article provides an overview of the role of cAMP as a second messenger, discusses bacterial cAMP subversion mechanisms, and reviews the evidence currently available on cAMP-based signaling in M. tuberculosis. Keywords: Adenylate cyclase, CREB, Cyclic AMP, Mycobacterium tuberculosis, Phosphodiesterase, Signal transduction, Virulence

cAMP signaling: An overview Cyclic AMP was discovered in 1957 by Dr. Earl Sutherland, who laid the foundation of the ‘second messenger’ concept during his studies on the mechanism of action of hormones1. cAMP regulates diverse physiological processes in both eukaryotes1-3 and prokaryotes4,5. Shortly after the discovery of cyclic AMP, cellular proteins comprising biosynthetic [adenylate cyclase (AC)] and the degradative [phosphodiesterase (PDE)] activities with this cyclic nucleotide have been identified6,7. In subsequent years it has been observed that cAMP performs its function by activating a cascade of kinases, the first of which was named protein kinase A (PKA)8 and since then a series of cAMP binding proteins have been identified such as cGMP-stimulated PDEs (PDE II), exchange proteins activated by cAMP (EPACs), cyclic nucleotide gated channels, and a recently identified PDE 10 (Ref.9-12). However, a major breakthrough in cAMP research has been achieved with discovery of PKA-regulated cAMP-response element binding protein (CREB), and the corresponding DNA binding element in the somatostatin gene13 and a cAMP regulatory domain in the phosphoenolpyruvate carboxykinase gene14. The discovery of CREB resulted in an improved understanding of cAMP __________________ *Correspondent author Telephone: +1-410-955-3507; Fax: +1- 410-614-8173 Email: [email protected]

signaling in eukaryotic cells, and since then additional cAMP-regulated genes have been identified. In eukaryotes, cAMP signaling begins with binding of extracellular first messengers such as a hormone, drug, or neurotransmitter to a G protein coupled receptor (GPCR). This binding event leads to exchange of GDP for GTP and subsequent dissociation of a stimulatory G protein α subunit (Gαs) from βγ subunit complex of seven transmembrane-spanning domain of GPCR. Release of Gαs subunit activates the cellular adenylate cyclase (AC) enzyme to catalyze the synthesis of cAMP from ATP15. AC activity is also regulated by binding of an inhibitory G protein α subunit (Gαi) which reduces AC activity. Some of the known Gαi coupled GPCR ligands include chemokines and leukotrienes16. cAMP level in the cell is not only regulated by AC activity, but also by the activity of another class of enzymes known as phosphodiesterases (PDEs), which hydrolyzes cAMP to 5´-AMP6. To date, in mammalians there are 10 known AC isoforms and 11 known PDE gene families and each is expressed in tissue-specific patterns. Upon AC activation in eukaryotic cells, the resulting cAMP goes on to serve as a second messenger. Elevated cAMP levels lead to PKA activation by promoting dissociation of its catalytic subunit. In turn, PKA phosphorylates various known target proteins including CREB at specific Ser and Thr residues. CREB in its phosphorylated form

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exhibits an altered affinity to its DNA binding elements and thus, participates in differential expression of target genes. Beyond CREB, additional alternative intracellular targets of cAMP such as reactive oxygen and nitrogen intermediate (ROIs and RNIs) production and phagosome maturation have been described. The presence of cAMP in prokaryotes was first reported in early 1960’s in Brevibacterium liquefaciens17 and in E. coli18. It has been observed that B. liquefaciens excretes significant amount of cAMP in the culture broth, whereas in E. coli the intracellular level of this cyclic nucleotide is inversely related to the presence of glucose and other carbon sources in the culture medium. Later it has been reported that cyclic AMP stimulates the synthesis of a number of inducible enzymes in E. coli, and that glucose-mediated repression of inducible enzyme synthesis (catabolite repression) is due to lowering of intracellular cyclic AMP levels in the presence of glucose19. Subsequently, cAMP was detected in several organisms, and the role of cAMP in regulating important metabolic pathways as well as virulence factors of prokaryotes has been reported4,5,20. With the advent of genome sequencing, the existing AC enzymes could be grouped into six different structural classes, and of these four are restricted to the prokaryotes. Adenylate cyclase of E. coli and related enteric bacteria belongs to AC class I, which are encoded by single copy genes and are involved in catabolite repression21,22. Conversely, AC toxins secreted by some pathogenic bacteria such as Bacillus anthracis, Bordetella pertussis, and Pseudomonas aeruginosa which elevate cAMP levels within the host cells during infection, comprise class II enzymes which are known to require single divalent metal ion for their catalytic activity23-26. Most widely distributed class of adenylate cyclases are the class III enzymes which are found in mycobacteria, archea, and eukaryotes. The mammalian GPCR-activated adenylate cyclases are also members of class III adenylate cyclase family. On the contrary, classes IV, V and VI of the cyclase family are rare, being found in Aeromonas, Prevotella, and Rhizobium species, respectively27. It appears that bacterial cAMP signaling pathways are simpler and involve fewer proteins than those in eukaryotes. cAMP signaling in bacteria has been first reported from E. coli where it has been observed that a cyclic nucleotide binding transcription factor known as CRP (cAMP receptor protein, also called CAP for

catabolite activator protein), a transcription activator protein, regulates the expression of lac operon responsible for metabolism of an alternate sugar, lactose, in the absence of glucose in the culture medium19. In an environment of a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP which in turn binds to a specific site adjacent to the lac promoter. In its DNA-bound form, CRP stimulates initiation of transcription by RNA polymerase at the adjacent promoter site, thus increasing the expression of lac operon. In the presence of glucose, cAMP concentration is reduced because of the inhibition of membrane-bound adenylate cyclase by a component of phosphotransferase system (PTS), EIIA; this suppresses the activation of CRP and thus reduces lac operon transcription28. Thus far, genes encoding adenylate cyclases have been found in virtually all prokaryotes except Bifidobacter longum and Tropheryma whipplei, indicating that cAMPmediated signaling is a near-universal phenomenon. In E. coli alone, CRP has been reported to activate transcription at more than 100 different promoters, suggesting that cAMP-mediated regulation of gene expression is not only required in higher organisms, but is also important in prokaryotes. The present review pertains to bacterially-mediated cAMP signal transduction subversion in macrophages, so a focus on the role of cAMP in bacterial pathogenicity has been dealt in the following sections. Subversion of cAMP signaling: Intoxication and modulation mechanisms of bacterial pathogens As discussed above, cAMP is an important regulator of many cellular processes, and it has been observed that host adenylate cyclases and phosphodiesterases governing the levels of cAMP in cells are intracellular targets of several bacterial toxins. Additionally, several humans pathogens have developed an ability to modulate host microbicidal capacity by altering potential targets of cAMP signaling such as release of reactive oxygen and nitrogen intermediates (ROIs and RNIs) and phagosome maturation (see review by Serezani et al.29 for details). Bacterial pathogens may increase host cAMP levels by two distinct mechanisms- (1) by direct injection of their adenylate cyclases into host cells (e.g., invasive adenylate cyclase of B. pertussis, edema factor of B. anthracis, ExoY of P. aeruginosa, and adenylate cyclase of Yersinia pestis); and (2) by regulating the activity of host adenylate cyclase through GPCR (e.g.,

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cholera toxin and pertussis toxin) (see review by Ahuja et al.20 for details). For example, entry of invasive adenylate cyclase toxin of B. pertussis into the host cell results in impaired chemotaxis, reduces oxidative response and killing capacity of neutrophils, macrophages30, and monocytes31; and induction of apoptosis in J774A.1 macrophages32. A rapid increase in the host cell cAMP levels due to this toxin facilitates nasopharyngeal colonization by the microbe during the first few days of infection33, and at later stages the cAMP signals are amplified by the activity of a second player, pertussis toxin itself, which catalyzes adenosine diphosphate (ADP) ribosylation of the host cell’s inhibitory Gαi subunit, resulting in activation of host adenylate cyclase. This further increase in host cAMP levels34 facilitates bacterial survival on host mucous membranes. Similarly, the edema factor of B. anthracis exhibits various effects on different cell types such as lipopolysaccharide-induced production of TNF-α and IL-6 by increasing intracellular cAMP levels in monocytes35; inhibition of neutrophils function36; effects on T-cell proliferation37, apoptosis38, diminished immune responsiveness39; and inhibition of phagocytosis, superoxide production and bactericidal activity of macrophages and neutrophils40,41. Similarly, ExoY of P. aeruginosa, adenylate cyclase of Y. pestis and cholera toxin exhibit various effects on the target cells as reviewed by Ahuja et al.20. cAMP and mycobacteria Identification of cAMP in mycobacteria and characterization of adenylate cyclases⎯Cyclic AMP has been first reported in Mycobacterium microti by Lowrie et al.42; and then discovered in several other slow- and fast-growing mycobacterial species42-46. Intrabacterial cyclic AMP levels in mycobacteria have been found significantly higher than the corresponding levels reported in other bacterial species grown under identical conditions43. Similarly, it has been observed that mycobacteria such as M. smegmatis also secretes significant amount of cAMP into the extracellular culture medium43. Although the molecular mechanisms of cAMP export are currently unknown, these observations indicate that mycobacteria possess high cAMP-synthesizing capacity and suggest that cAMP may serve as both an extra- and intracellular signaling molecule in members of the genus.

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Adenylate cyclase activity has been first reported in cell-free extracts of mycobacteria in the late-1970s by Padh and Venkitasubraminan43,44. Later, with the advent of genome sequences of M. tuberculosis and related mycobacteria, the presence of multiple adenylate cyclase paralogues within the genomes has been observed. For example, M. tuberculosis CDC1551 has 17 AC genes, M. avium 12 ACs, and M. marinum 31 ACs. Several of AC enzymes from M. tuberculosis have now been characterized biochemically47-57. In general these studies have shown that each of the characterized AC is biochemically distinct, a finding which suggests that cAMP production is driven by different ACs under different conditions. Indeed, the in vitro activities of mycobacterial ACs have been shown to be modulated by different physiological conditions such as low pH (Rv1264, Rv1647), detergent (Rv1647), bicarbonate/CO2 (Rv1318c, Rv1319c, Rv1320c and Rv3645), fatty acid (Rv2212) as well as by allosteric regulation by the associated domains of AC itself (Rv1318c, Rv1319c, Rv1320c, Rv3645)58. These observations point towards an orchestrated strategy developed by mycobacteria to regulate cellular cAMP levels58. However, characterization of intracellular cAMP levels in mycobacteria under different stresses, as well as the specific roles of different ACs in maintaining cAMP levels under stress conditions remain to be determined. Intracellular cAMP signaling in mycobacteria⎯As described above, in prokaryotes cAMP signaling involves differential activity of a transcription factor, cAMP receptor binding protein (CRP), which in turn regulates the expression of cAMP-dependent genes. Although, the specific environmental conditions which alter mycobacterial intracellular cAMP levels are not clearly understood, M. tuberculosis CRP homolog encoded by a mycobacterial gene Rv3676 has recently been described59,60. Rv3676 contains an N-terminal cAMP-binding domain and a C-terminal DNA-binding domain. Using the systematic evolution of ligands by exponential enrichment (SELEX) approach, a consensus Rv3676-binding site has been predicted which exhibites significant homology with the known E. coli CRP-binding sequence. Using bioinformatics, several mycobacterial promoters that contain the Rv3676-binding sequence have been identified. It has been observed that cAMP increases the affinity of Rv3676 for its cognate DNA sequence by an allosteric conformational shift60. However, in

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this study neither a direct binding of Rv3676 with cAMP, nor in vivo regulation of the identified promoters by cAMP has been demonstrated. However, in a separate study it has been observed that several mycobacterial genes were underexpressed in Rv3676 deletion mutants compared to their expression levels in the corresponding wild-type strain indicating the role of cAMP signaling via Rv3676 in regulating of mycobacterial gene expression61. Despite the presence of cAMP in several other mycobacterial species, little is known about cAMPmediated gene regulation beyond the preliminary work done in M. tuberculosis. Phenotypically, it has been reported that elevated intracellular cAMP levels in M. smegmatis cause a significant increase in synthesis of phospholipids, cardiolipin, and phosphatidylinositol mannosides62,63. Recently, it has been observed by proteomic analysis of M. bovis BCG that several physiologically important gene products accumulate in the presence of exogenous cAMP and that the accumulation is significantly more when bacteria are grown in the presence of cAMP and low oxygen64. Recently we have shown that cAMPstimulated CRP regulates the expression of a transcription factor encoded by whiB1, which belongs to whiB-like family of M. tuberculosis65. Regulation of mycobacterial cAMP levels⎯As discussed above, cAMP regulates the expression of genes which otherwise need to be strictly regulated. This suggests that cAMP production in cells is also strictly regulated. cAMP levels in bacteria may be regulated by several means, such as conditional expression of AC, PDE genes or by post-translational control mechanisms governing the activities of expressed ACs, and/or PDEs. Though, mycobacteria exhibit high intrabacterial cAMP levels, the mechanism for maintenance of critical threshold levels of cAMP is unknown. Using an in silico search for bacterial class III cNMP phosphodiesterases in mycobacteria, it has been observed that a mycobacterial gene product, Rv0805 contains a PDElike domain. PDE activity of Rv0805 has been confirmed by overexpression in E. coli and M. smegmatis and demonstration of cAMP-hydrolyzing activity in vitro and in vivo66. Recently, it has been observed that Rv0805 is 150-fold more active in hydrolyzing 2´,3´ cAMP than 3´,5´ cAMP67 thus indicating that Rv0805 has acquired an ability to control the levels of multiple small signaling

molecules in mycobacteria. Despite the presence of a gene encoding PDE in mycobacteria, the in vivo role of Rv0805 in maintaining cAMP levels in mycobacteria remains to be determined. Also, it remains possible that mycobacteria possess multiple PDEs to provide conditional regulatory modulation of cAMP degradation. Differential expression of genes encoding ACs and PDEs under different growth conditions (as observed by microarray analyses58) may provide an alternate strategy to regulate cAMP levels in mycobacteria under different conditions, and indeed, gene expression modulation may be coupled with posttranslational modification of mycobacterial ACs and PDEs under these physiological conditions. Thus, microarray expression profiling alone is not sufficient to estimate cAMP accumulation levels. Yet another factor which may play an important role is subcellular compartmentalization of cAMP as it is clear that M. tuberculosis and M. smegmatis maintain both intra- and extra-cellular cAMP pools. Although the sub-cellular localization of mycobacterial ACs have been predicted largely based on bioinformatics analysis, the presently available proteomic data suggest several anomalies in the experimentally determined locations compared with those predicted68. For example, Rv0386 and Rv1358 have been identified in the cell wall and cell membrane despite not having any predicted transmembrane domains. Similarly, Rv1318c has been observed to accumulate in the cytosol regardless of the presence of multiple transmembrane domains68. These localization patterns thus suggest that our knowledge about the molecular basis of the localization of mycobacterial ACs to different cellular fractions is still poor. cAMP and mycobacterial pathogenesis⎯As discussed above, subversion of host cAMP levels is a major virulence strategy adopted by several human pathogens. However, a direct role of cAMP in mycobacterial pathogenesis has not been established. Studies of well-known attenuated mutants of virulent mycobacteria have not suggested a role for cAMPbased pathogenesis, for example, both the nonpathogenic human vaccine M. bovis BCG and its pathogenic counterpart wild-type M. bovis share all of the identified AC genes. Though an early report suggests that M. microti utilizes cAMP secretion to prevent phago-lysosomal fusion42,69, it remains to be

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determined whether other mycobacterial species including M. tuberculosis influence host cells by secretion of cAMP. Because of the multiplicity of AC genes in M. tuberculosis, traditional mutagenesis studies are frequently inconclusive in addressing the question of cAMP-based pathogenesis mechanism in mycobacteria. For example, it has recently been reported that deletion of two mycobacterial AC genes, Rv1264 and Rv1625c, do not result in growth attenuation in mice70,71. However, cAMP levels in these two mutant strains are not estimated, and therefore, the findings do not rule out the possibility that other ACs, or a combination of these and other ACs, play a role in M. tuberculosis pathogenicity. Since M. tuberculosis contains multiple AC genes, potential redundancy in their activities remains a confounding factor in studies which alter the activity of single AC genes. Therefore, a direct role of cAMP in M. tuberculosis pathogenicity can better be studied by using mutants in downstream signaling components. Mycobacterial CRP, Rv3676, is one such component, and it has indeed been observed that deletion of Rv3676 leads to an attenuated growth phenotype in macrophages and in mice61. Moreover, accumulation of several inactivating mutations in CRP homologue of several M. bovis BCG strains provides further circumstantial evidence to link cAMP signaling with pathogenicity in mycobacteria59. Subversion of cAMP levels in mouse peritoneal macrophages after infection with live mycobacteria, but not with latex beads or dead bacilli, further corroborate that only metabolically active bacteria can alter host cAMP levels69. Though, these studies provide important circumstantial evidence that the source of cAMP during infection of mouse macrophages may be mycobacterial, rigorous proof that bacteria contribute to intramacrophage cAMP pool has not been established. Moreover, the effect of increased cAMP levels in infected macrophages on the survival of intracellular mycobacteria also remains to be determined. Recently, in a study by Kalamidas et al. it has been observed that cAMP signaling inhibitors SQ22536 (host AC inhibitor) and H89 (PKA inhibitor) inhibit survival of M. tuberculosis H37Rv in J774 macrophages indicating that reduced intramacrophage cAMP levels (as well as reduced PKA activation) correlate with poorer mycobacterial survival in host macrophages. The observation that cAMP is known to inhibit actin assembly and

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phagosome acidification in the presence of latex beads, prompted the authors to hypothesize these inhibitors may promote phago-lysosome fusion and phagosome acidification leading to diminished survival of infecting bacilli72. However, direct evidence of these events in the host macrophages infected with mycobacteria is still awaited. Conversely, in another study, different cAMP levels in host macrophages were observed during infection with different pathogenic mycobacteria73. Infection by an opportunistic pathogen, M. avium, has been associated with less and by non-pathogen, M. smegmatis, resulted in more intramacrophage cAMP. The authors suggested that sustained elevation of macrophage cAMP levels during M. smegmatis infection leads to activation of host adenylate cyclases and subsequently increased overexpression of the host cytokine, TNF-α, through a phospho-CREBdependent mechanism, and increased TNF-α leads to better clearance of non-pathogenic M. smegmatis in comparison to its pathogenic counterpart, M. avium73. Conclusion and perspectives M. tuberculosis is an intracellular pathogen which has developed a capacity to block phagosome maturation pathways that are bactericidal to other ingested organisms. Several mechanisms have been implicated in the pathogen’s interference with phagosome-lysosome fusion including molecular mimicry by mannose-capped LAM simulating phosphatidylinositol-3-phosphate binding effectors, secretion of a eukaryotic-like serine-threonine protein kinase, and inhibition of vesicular trafficking by bacterial lipids. At the tissue level, M. tuberculosis elicits an inappropriate immune response that results in caseous necrosis and formation of solid granulomas. These lesions which are avascular and possibly hypoxic may allow chronic contained infection. M. tuberculosis contains multiple ACs, a feature shared by pathogenic mycobacteria such as M. avium (12 ACs) and M. marinum (31 ACs). In contrast, E. coli, P. aeruginosa, Corynebacterium glutamicum, and Streptomyces coelicolor have only one AC27. Though we have a fair knowledge about the biochemistry of enzymes involved in cAMP synthesis and degradation in mycobacteria, there are several key issues as given in Box 1 which need to be addressed for a better understanding of the role of this

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BOX 1- Key issues on role of cAMP in physiology and pathology of M. tuberculosis • What is the role of multiple ACs in mycobacteria? • What are the cAMP regulons in mycobacteria and how do they affect mycobacterial physiology? • What are the levels of cAMP in mycobacteria under different growth conditions? • Do mycobacteria also secrete ACs? • Are host signaling events subverted by direct injection of mycobacterial cAMP into host cells? If so, how? • Does cAMP enhance inflammation and granuloma formation in the host to provide a sanctuary to hide and an opportunity for transmission by promoting cavity formation? • What are the host responses to mycobacterial cAMP? • Is there differential activation of host PDEs following mycobacterial infection? • Does high extracellular concentration of cAMP play any role in cell-cell crosstalk in mycobacteria (similar to social amoeba, Dictyostelium discoideum)? second messenger in physiology and pathology of M. tuberculosis. Additionally, studies focused on the cascade of events initiated by M. tuberculosis-driven modulation of mycobacterial as well as host cell cAMP signaling are likely to reveal several important consequences of signal transduction subversion in these biological entities. Acknowledgement The support of NIH grants AI37876, AI36973, and AI30036 is gratefully acknowledged. References 1 Robison G A, Butcher R W & Sutherland E W, Cyclic AMP, Annu Rev Biochem, 37 (1968) 149. 2 Pittenger C, Huang Y Y, Paletzki R F, Bourtchouladze R, Scanlin H, Vronskaya S & Kandel E R, Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory, Neuron, 34 (2002) 447. 3 Torgersen K M, Vang T, Abrahamsen H, Yaqub S & Tasken K, Molecular mechanisms for protein kinase A-mediated modulation of immune function, Cell Signal, 14 (2002) 1. 4 Botsford J L & Harman J G, Cyclic AMP in prokaryotes, Microbiol Rev, 56 (1992) 100. 5 Rickenberg H V, Cyclic AMP in prokaryotes, Annu Rev Microbiol, 28 (1974) 353. 6 Butcher R W & Sutherland E W, Adenosine 3',5'-phosphate in biological materials. I. Purification and properties of cyclic 3',5'-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3',5'-phosphate in human urine, J Biol Chem, 237 (1962) 1244. 7 Rall T W & Sutherland E W, Adenyl cyclase. II. The enzymatically catalyzed formation of adenosine 3',5'phosphate and inorganic pyrophosphate from adenosine triphosphate, J Biol Chem, 237 (1962) 1228. 8 Krebs E G, Protein kinases, Curr Top Cell Regul, 5 (1972) 99.

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