- Email: [email protected]
Cell regulation
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Cell regulation Editorial overview Lucia B Rothman-Denes and Claude Parsot Current Opinion in Microbiology 2008, 11:75–77 Available online 21st March 2008 1369-5274/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.mib.2008.02.017
Lucia B Rothman-Denes Department of Molecular Genetics and Cell Biology, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA e-mail: [email protected]
Lucia B Rothman-Denes is Professor in the Department of Molecular Genetics and Cell Biology and member of the Committees on Genetics and Microbiology at the University of Chicago. Her research focuses on mechanisms of RNA polymerase-promoter recognition, regulation of transcription, and host– phage interactions. Claude Parsot1,2 1
Institut Pasteur, Unite´ de Pathoge´nie Microbienne Mole´culaire, 25 rue du Dr Roux, F-75015, Paris, France 2 INSERM U786, F-75015, Paris, France e-mail: [email protected]
Claude Parsot is Associate Professor at the Pasteur Institute in Paris (France). His research interests are focused on the virulence plasmidencoded type III secretion system used by Shigella spp. to invade the colonic epithelium in humans.
This issue of Current Opinion in Microbiology is focused on diversity, both in topics presented – replication, transcription, translation, and protein activity – and in the mechanisms used to control these processes in different organisms. That microorganisms are adapted to their environment is common sense, otherwise they would not be there. Those microorganisms that can withstand different environments adjust the expression of specific sets of genes and the activity of proteins to the nature and composition of the external milieu. In many cases the same biological cue, such as the presence or absence of a nutrient, is dealt with different strategies in different organisms. These different strategies, which might result from varied constraints, have in many cases profound implications on the evolution of microbes, their phages, and their hosts. Regulation of the synthesis of an amino acid should be a simple issue. Merino, Jensen, and Yanofsky embark us on a journey of the regulation of the tryptophan biosynthetic genes to discover amazing diversities in gene organization and their control mechanisms among bacterial species. These mechanisms act on initiation and elongation of both transcription and translation; they are mediated by proteins, ribosomes, charged and uncharged tRNAs; and they respond to the availability of tryptophan or indoleglycerol phosphate. Furthermore, different control mechanisms are often combined within the same organism. The authors point our attention to the acquisition of tryptohan biosynthetic genes by lateral gene transfer, a term usually coined for virulence genes, in relation with the various roles of tryptophan. Likewise, catabolite repression is a common textbook case for gene regulation, and we all learned that bacteria exposed to several carbon sources utilize preferentially one of these sources. Deutscher describes, at the molecular level, mechanisms mediating carbon catabolite repression and shows that they are not only diverse among bacteria, but again that multiple modes of regulation exist within the same bacterium. These mechanisms rely on both the exclusion of inducers, that is, the inhibition of the uptake of the less-preferred carbon sources, and global as well as specific transcription regulators. All cells must complete replication and segregation of their chromosomes while attaining a specific mass before completing cell division. This is accomplished through processes that require both temporal and spatial coordination. Analysis of these processes has been aided by the recent development of cell biology tools for bacteria. Haeusser and Levin describe the mechanisms coordinating these processes in Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis). The emerging picture indicates the existence of an orderly progression of events, coupled with flexible coordination through multiple interactions, both weak and strong ones. Research during the past two decades has provided insights at the molecular level of the mechanism
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Current Opinion in Microbiology 2008, 11:75–77
76 Cell regulation
by which (p)ppGpp, discovered 40 years ago, regulates transcription in Gram-negative and, more recently, Grampositive bacteria to mediate the stringent response. Srivatasan and Wang outline recent progress, including the involvement of (p)ppGpp in regulation of translation and DNA replication and repair, with concomitant effects on cell physiology, genome stability, and evolution. The activity of adenine methyltransferases leads essentially to two different outputs on specific sequences, the double stranded DNA being either hemi-methylated or fully methylated. Low and Casadesus describe how such a simple mechanism is used to control, both spatially and temporally, a variety of processes in bacteria such as the coupling of cell cycle regulators to the progression of the replication fork, phase variation, and the activation and the repression of gene transcription by specific and even global regulators. Here, diversity is at stake not in the mechanism (DNA methylated or not), but in the consequences and the biological processes that are controlled. Several highly abundant proteins, such as H-NS, Fis, HU, Dps, and StpA are responsible for condensation of the bacterial chromosome into a nucleoid. Although the exact mechanism of DNA condensation is not known, nucleoid proteins are responsible for regulating gene expression in a global manner. Fang and Rimsky describe the properties of H-NS, which binds and spreads along AT-rich DNA to silence bacterial gene expression, highlighting the recently discovered role of H-NS in facilitating the acquisition of horizontally transferred genes. Bacteria have one or more sigma-70 family members, with two conserved domains that confer specificity of promoter recognition to the core RNA polymerase. Campbell, Westlake, and Darst provide a structural perspective of the interaction between sigma factors and anti-sigma factors. Although the targets of anti-sigma factors are conserved, a diversity of anti-sigma factor structures and multipartite interaction mechanisms is used to occlude sigma factor determinants of core binding. For macromolecular complexes, such as the flagellar apparatus and the type III secretion apparatus involved in transit of proteins across the bacterial envelope, timing is required to adjust expression of flagellin and substrates of the secretion apparatus to the completion or activation of the apparatus. The constraints are seemingly the same; however, Brutinel and Yahr show the variety of mechanisms used to couple transcription of some genes to the secretion activity through regulatory cascades involving an assortment of activators (or sigma factors), anti-activators, co-activators, and anti-anti-activators. Talking about diversity, chemical modifications of tRNAs outnumber codons, not to say tRNA genes, and there are more genes devoted to tRNA modifications than genes encoding tRNAs. Gustillo, Vendeix, and Agris explain how modifications of two positions of the tRNA anticCurrent Opinion in Microbiology 2008, 11:75–77
odon, which differ in tRNAs recognizing rare or common codons, control translation. These modifications permit recognition by aminoacyl-tRNA synthetases, binding to some codons and prevention of frameshifting. Who could think that other tRNA modifications have been selected for decoration? Diversity in the means does not exclude universality of fundamental processes, such as elongation of transcription and translation. Capitalizing on recent advances on the structure of the ribosome and on new kinetic analysis, Johansson, Lovmar, and Ehrenberg use mathematical modeling to confront experimental results obtained in vitro and in vivo and revisit the mechanisms underlying the tradeoff between rate and accuracy in translation. This formal approach pushes interpretations of experimental data to their limits, thereby eliciting new questions. Bacteria must regulate their membrane lipid composition to survive under different environments and to avoid energy expenditure. Enzymes involved in fatty acid biosynthesis are highly conserved, but the means used to control the flux of metabolites in the pathway are different. In E. coli, the activities of the enzymes involved in the lipid biosynthetic pathway are regulated. By contrast, as Schujman and de Mendoza describe, the regulation of lipid biosynthesis in B. subtilis occurs at the level of enzyme biosynthesis. Modulation of enzymatic activity by phosphorylation is a common theme in signaling pathways, particularly (but not solely) in eukaryotic organisms. Rhode et al. describe the remarkable versatility of the Saccharomyces cerevisiae Tor kinases in modulating a wide range of cellular signaling pathways in response to nutrient deprivation. Sometimes, things are not what they look like at the first glance. Fajardo and Martinez describe the potential duality of antibiotics and other molecules that not only act as inhibitors of growth but also as signaling molecules inducing specific responses at subinhibitory concentrations. This expands considerably the diversity of strategies that microorganisms would use to communicate between themselves and shed new light on the ecological role of antibiotics. The regulation by visible light of cellular processes is mediated by photoreceptors that are present in both phototrophic and non-phototrophic microorganisms. Genetic and biochemical approaches have revealed a variety of photosensory receptors. Purcell and Crosson review the chemistry, structure, and physiological role of photosensory signal proteins. Besides their well-defined role in the regulation of the expression of bacteriorhodopsin and the photosynthetic machinery, these proteins are involved in photoprotective responses, bacterial development, localization in the environment, and virulence. The co-evolution of pathogens and their hosts resembles an arms race in which each partner is trying to take control of the other. In the case of plant-pathogenic bacteria, this www.sciencedirect.com
Editorial overview Rothman-Denes 77
has led to the selection and accumulation of a plethora of effectors that are injected into plant cells to subdue host defenses. Zhou and Chai present the characterization of the activities and the targets of some of these effectors, showing the diversity of strategies used by bacteria to alter innate immunity signaling pathways in plants. The study of bacteriophages spearheaded the development of molecular biology and the elucidation of transcriptional regulation, DNA replication, and assembly of macromolecular structures mechanisms. Nechaev and Severinov describe a variety of novel mechanisms used by phages to co-opt or inhibit host replication, transcription, and translation machineries. As in the case of host–pathogen interactions, bacteria and their phages have evolved
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mechanisms to counteract each other. The recent availability of a large set of bacterial genome sequences combined with biochemical and genetic analyses provides an emerging picture of the impact of phages on bacterial evolution. The study of essential processes in a relatively small number of model organisms, such as the bacteria E. coli and B. subtilis, the phages lambda and T4, and the yeast Saccharomyces cerevisiae, indicates that various solutions exist in nature to deal with similar environmental cues. There is much to learn from diversity; investigating other organisms will, surely, reveal a greater repertoire of mechanisms.
Current Opinion in Microbiology 2008, 11:75–77
Cell regulation Editorial overview Lucia B Rothman-Denes and Claude Parsot Current Opinion in Microbiology 2008, 11:75–77 Available online 21st March 2008 1369-5274/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.mib.2008.02.017
Lucia B Rothman-Denes Department of Molecular Genetics and Cell Biology, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA e-mail: [email protected]
Lucia B Rothman-Denes is Professor in the Department of Molecular Genetics and Cell Biology and member of the Committees on Genetics and Microbiology at the University of Chicago. Her research focuses on mechanisms of RNA polymerase-promoter recognition, regulation of transcription, and host– phage interactions. Claude Parsot1,2 1
Institut Pasteur, Unite´ de Pathoge´nie Microbienne Mole´culaire, 25 rue du Dr Roux, F-75015, Paris, France 2 INSERM U786, F-75015, Paris, France e-mail: [email protected]
Claude Parsot is Associate Professor at the Pasteur Institute in Paris (France). His research interests are focused on the virulence plasmidencoded type III secretion system used by Shigella spp. to invade the colonic epithelium in humans.
This issue of Current Opinion in Microbiology is focused on diversity, both in topics presented – replication, transcription, translation, and protein activity – and in the mechanisms used to control these processes in different organisms. That microorganisms are adapted to their environment is common sense, otherwise they would not be there. Those microorganisms that can withstand different environments adjust the expression of specific sets of genes and the activity of proteins to the nature and composition of the external milieu. In many cases the same biological cue, such as the presence or absence of a nutrient, is dealt with different strategies in different organisms. These different strategies, which might result from varied constraints, have in many cases profound implications on the evolution of microbes, their phages, and their hosts. Regulation of the synthesis of an amino acid should be a simple issue. Merino, Jensen, and Yanofsky embark us on a journey of the regulation of the tryptophan biosynthetic genes to discover amazing diversities in gene organization and their control mechanisms among bacterial species. These mechanisms act on initiation and elongation of both transcription and translation; they are mediated by proteins, ribosomes, charged and uncharged tRNAs; and they respond to the availability of tryptophan or indoleglycerol phosphate. Furthermore, different control mechanisms are often combined within the same organism. The authors point our attention to the acquisition of tryptohan biosynthetic genes by lateral gene transfer, a term usually coined for virulence genes, in relation with the various roles of tryptophan. Likewise, catabolite repression is a common textbook case for gene regulation, and we all learned that bacteria exposed to several carbon sources utilize preferentially one of these sources. Deutscher describes, at the molecular level, mechanisms mediating carbon catabolite repression and shows that they are not only diverse among bacteria, but again that multiple modes of regulation exist within the same bacterium. These mechanisms rely on both the exclusion of inducers, that is, the inhibition of the uptake of the less-preferred carbon sources, and global as well as specific transcription regulators. All cells must complete replication and segregation of their chromosomes while attaining a specific mass before completing cell division. This is accomplished through processes that require both temporal and spatial coordination. Analysis of these processes has been aided by the recent development of cell biology tools for bacteria. Haeusser and Levin describe the mechanisms coordinating these processes in Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis). The emerging picture indicates the existence of an orderly progression of events, coupled with flexible coordination through multiple interactions, both weak and strong ones. Research during the past two decades has provided insights at the molecular level of the mechanism
www.sciencedirect.com
Current Opinion in Microbiology 2008, 11:75–77
76 Cell regulation
by which (p)ppGpp, discovered 40 years ago, regulates transcription in Gram-negative and, more recently, Grampositive bacteria to mediate the stringent response. Srivatasan and Wang outline recent progress, including the involvement of (p)ppGpp in regulation of translation and DNA replication and repair, with concomitant effects on cell physiology, genome stability, and evolution. The activity of adenine methyltransferases leads essentially to two different outputs on specific sequences, the double stranded DNA being either hemi-methylated or fully methylated. Low and Casadesus describe how such a simple mechanism is used to control, both spatially and temporally, a variety of processes in bacteria such as the coupling of cell cycle regulators to the progression of the replication fork, phase variation, and the activation and the repression of gene transcription by specific and even global regulators. Here, diversity is at stake not in the mechanism (DNA methylated or not), but in the consequences and the biological processes that are controlled. Several highly abundant proteins, such as H-NS, Fis, HU, Dps, and StpA are responsible for condensation of the bacterial chromosome into a nucleoid. Although the exact mechanism of DNA condensation is not known, nucleoid proteins are responsible for regulating gene expression in a global manner. Fang and Rimsky describe the properties of H-NS, which binds and spreads along AT-rich DNA to silence bacterial gene expression, highlighting the recently discovered role of H-NS in facilitating the acquisition of horizontally transferred genes. Bacteria have one or more sigma-70 family members, with two conserved domains that confer specificity of promoter recognition to the core RNA polymerase. Campbell, Westlake, and Darst provide a structural perspective of the interaction between sigma factors and anti-sigma factors. Although the targets of anti-sigma factors are conserved, a diversity of anti-sigma factor structures and multipartite interaction mechanisms is used to occlude sigma factor determinants of core binding. For macromolecular complexes, such as the flagellar apparatus and the type III secretion apparatus involved in transit of proteins across the bacterial envelope, timing is required to adjust expression of flagellin and substrates of the secretion apparatus to the completion or activation of the apparatus. The constraints are seemingly the same; however, Brutinel and Yahr show the variety of mechanisms used to couple transcription of some genes to the secretion activity through regulatory cascades involving an assortment of activators (or sigma factors), anti-activators, co-activators, and anti-anti-activators. Talking about diversity, chemical modifications of tRNAs outnumber codons, not to say tRNA genes, and there are more genes devoted to tRNA modifications than genes encoding tRNAs. Gustillo, Vendeix, and Agris explain how modifications of two positions of the tRNA anticCurrent Opinion in Microbiology 2008, 11:75–77
odon, which differ in tRNAs recognizing rare or common codons, control translation. These modifications permit recognition by aminoacyl-tRNA synthetases, binding to some codons and prevention of frameshifting. Who could think that other tRNA modifications have been selected for decoration? Diversity in the means does not exclude universality of fundamental processes, such as elongation of transcription and translation. Capitalizing on recent advances on the structure of the ribosome and on new kinetic analysis, Johansson, Lovmar, and Ehrenberg use mathematical modeling to confront experimental results obtained in vitro and in vivo and revisit the mechanisms underlying the tradeoff between rate and accuracy in translation. This formal approach pushes interpretations of experimental data to their limits, thereby eliciting new questions. Bacteria must regulate their membrane lipid composition to survive under different environments and to avoid energy expenditure. Enzymes involved in fatty acid biosynthesis are highly conserved, but the means used to control the flux of metabolites in the pathway are different. In E. coli, the activities of the enzymes involved in the lipid biosynthetic pathway are regulated. By contrast, as Schujman and de Mendoza describe, the regulation of lipid biosynthesis in B. subtilis occurs at the level of enzyme biosynthesis. Modulation of enzymatic activity by phosphorylation is a common theme in signaling pathways, particularly (but not solely) in eukaryotic organisms. Rhode et al. describe the remarkable versatility of the Saccharomyces cerevisiae Tor kinases in modulating a wide range of cellular signaling pathways in response to nutrient deprivation. Sometimes, things are not what they look like at the first glance. Fajardo and Martinez describe the potential duality of antibiotics and other molecules that not only act as inhibitors of growth but also as signaling molecules inducing specific responses at subinhibitory concentrations. This expands considerably the diversity of strategies that microorganisms would use to communicate between themselves and shed new light on the ecological role of antibiotics. The regulation by visible light of cellular processes is mediated by photoreceptors that are present in both phototrophic and non-phototrophic microorganisms. Genetic and biochemical approaches have revealed a variety of photosensory receptors. Purcell and Crosson review the chemistry, structure, and physiological role of photosensory signal proteins. Besides their well-defined role in the regulation of the expression of bacteriorhodopsin and the photosynthetic machinery, these proteins are involved in photoprotective responses, bacterial development, localization in the environment, and virulence. The co-evolution of pathogens and their hosts resembles an arms race in which each partner is trying to take control of the other. In the case of plant-pathogenic bacteria, this www.sciencedirect.com
Editorial overview Rothman-Denes 77
has led to the selection and accumulation of a plethora of effectors that are injected into plant cells to subdue host defenses. Zhou and Chai present the characterization of the activities and the targets of some of these effectors, showing the diversity of strategies used by bacteria to alter innate immunity signaling pathways in plants. The study of bacteriophages spearheaded the development of molecular biology and the elucidation of transcriptional regulation, DNA replication, and assembly of macromolecular structures mechanisms. Nechaev and Severinov describe a variety of novel mechanisms used by phages to co-opt or inhibit host replication, transcription, and translation machineries. As in the case of host–pathogen interactions, bacteria and their phages have evolved
www.sciencedirect.com
mechanisms to counteract each other. The recent availability of a large set of bacterial genome sequences combined with biochemical and genetic analyses provides an emerging picture of the impact of phages on bacterial evolution. The study of essential processes in a relatively small number of model organisms, such as the bacteria E. coli and B. subtilis, the phages lambda and T4, and the yeast Saccharomyces cerevisiae, indicates that various solutions exist in nature to deal with similar environmental cues. There is much to learn from diversity; investigating other organisms will, surely, reveal a greater repertoire of mechanisms.
Current Opinion in Microbiology 2008, 11:75–77