Functional Modulation Of Escherichia Coli Rna Polymerase

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Annu. Rev. Microbiol. 2000. 54:499–518 c 2000 by Annual Reviews. All rights reserved Copyright

FUNCTIONAL MODULATION OF ESCHERICHIA COLI RNA POLYMERASE Annu. Rev. Microbiol. 2000.54:499-518. Downloaded from arjournals.annualreviews.org by INSERM-multi-site account on 03/04/09. For personal use only.

Akira Ishihama National Institute of Genetics, Department of Molecular Genetics, Mishima, Shizuoka 411-8540, Japan; e-mail: [email protected]

Key Words transcription apparatus, sigma factor, transcription factor, stationary phase ■ Abstract The promoter recognition specificity of Escherichia coli RNA polymerase is modulated by replacement of the σ subunit in the first step and by interaction with transcription factors in the second step. The overall differentiated state of ∼2000 molecules of the RNA polymerase in a single cell can be estimated after measurement of both the intracellular concentrations and the RNA polymerase-binding affinities for all seven species of the σ subunit and 100–150 transcription factors. The anticipated impact from this line of systematic approach is that the prediction of the expression hierarchy of ∼4000 genes on the E. coli genome can be estimated. CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 MODULATION OF RNA POLYMERASE SPECIFICITY BY REPLACEMENT OF THE σ SUBUNIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 SIGMA REPLACEMENT DURING GROWTH TRANSITION FROM EXPONENTIAL TO STATIONARY PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 LEVEL AND ACTIVITY CONTROL OF SIGMA-S . . . . . . . . . . . . . . . . . . . . . . . 503 ACTIVITY CONTROL OF THE SIGMA SUBUNITS BY ANTI-SIGMA FACTORS 507 MODULATION OF RNA POLYMERASE SPECIFICITY BY TRANSCRIPTION FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 FACTORS AFFECTING SELECTIVE UTILIZATION OF TRANSCRIPTION APPARATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 MULTIPLE PATHWAYS FOR STATIONARY-PHASE ADAPTATION . . . . . . . . . . 510 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

INTRODUCTION The RNA polymerase of Escherichia coli is composed of the core enzyme (subunit composition, α 2ββ’) with the catalytic activity of RNA polymerization, and one of the seven different species of σ subunit, each responsible for recognition 0066-4227/00/1001-0499$14.00

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of a specific set of promoters (28, 29, 31, 40). The total number of core enzyme molecules in a growing E. coli cell is ∼2000 (38, 43), which is less than the total number of genes (∼4000) on the E. coli genome (7). Together these findings accentuate the importance of RNA polymerase to choose which genes to transcribe and how often (39, 40). Because replacement of the σ subunit is the most efficient way to alter the promoter recognition properties of the transcription apparatus, the replacement of one σ species of core enzyme-associated σ subunit by another is believed to be the major mechanism for switching of the transcription pattern. Along this line, competition between available σ subunits should be a key determinant of which group of genes is transcribed (22, 108; H Maeda, N Fujita, A Ishihama, submitted for publication). To test the σ competition model, quantitative and comparative measurements of the intracellular concentrations and the core enzyme-binding affinities of all seven σ subunits are absolutely required. The holoenzyme alone is able to recognize the simple promoters of genes that are constitutively expressed and to initiate transcription at constant rates. Most of the genes in bacteria are, however, subject to regulation in response to changes in environmental conditions. Thus, for transcription of the majority of E. coli genes, one or more additional accessory factors are required (39, 40). Among the same group of genes under the control of a single σ species, the order of transcription level is therefore determined by the promoter strength and the initiation efficiency, assisted or inhibited by transcription factors. From the genome sequence of E. coli, the total number of DNA-binding proteins that more or less influence transcription can be estimated to be ∼240–260 (85; N Fujita, unpublished data). Most of these DNA-binding proteins, which either activate or repress transcription of specific genes, interact directly with the RNA polymerase and modulate its specificity of transcription initiation (and elongation in some cases). The known transcription factors can be classified into groups by their structure and mode of function (40–42). Overall, therefore, the transcription specificity of RNA polymerase core enzyme is modulated in two steps: by molecular interaction with the σ factors in the first step and with the transcription factors, usually DNA bound, in the second step. The expression hierarchy of the ∼4000 genes on the E. coli genome must be determined to a great extent by the relative levels of transcription apparatus composed of core enzymes combined with different σ subunits and different transcription factors. This review summarizes our up-to-date knowledge of such functional differentiation of RNA polymerase in E. coli, focusing on its alteration during the growth phase transitions of E. coli cultures.

MODULATION OF RNA POLYMERASE SPECIFICITY BY REPLACEMENT OF THE σ SUBUNIT Seven different species of σ subunits, σ 70, σ N (also called σ 54), σ S (σ 38), σ H (σ 32), σ F (σ 28), σ E (σ 24), and σ FecI, have been identified in E. coli (28, 29, 31, 40), each participating in transcription of a specific set of genes (Figure 1, see color insert).

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Most of the housekeeping genes expressed during exponential-phase growth are transcribed by the holoenzyme containing σ 70 (the rpoD gene product), while the holoenzyme Eσ S is essential for transcription of some stationary-phase specific genes (32, 65). Stress response genes are transcribed by RNA polymerase holoenzymes containing alternative minor σ subunits. The holoenzyme Eσ N transcribes those genes, which are activated by a deficiency of nitrogen (70) and some other stress response genes (90); the holoenzyme Eσ H transcribes the genes for heat shock proteins (103); Eσ F is needed for expression of the third wave of flagellar and chemotaxis genes (30); the holoenzyme Eσ E is responsible for transcription of genes whose products deal with protein defects such as misfolded proteins in the periplasm, caused, for example, by heat shock (20, 81, 82, 87); and the fecI gene product, which was originally identified as a positive regulatory gene for the ferric citrate transport system (80), is now known to be a member of the extracytoplasmic function subfamily of σ factors (3, 67) based on its protein sequence (hereafter referred to as σ FecI) and is involved in transcriptional activation of the fec operon (19, 25). The intracellular concentration of RNA polymerase in the steady state of growing E. coli W3350 cells is maintained at a constant level that is characteristic of the rate of cell growth (38, 43). In a rich medium, the total number of core enzyme molecules is ∼2000 per genome equivalent of DNA, among which about one third are disengaged from the DNA. Because RNA chain elongation is catalyzed by core enzyme without an associated σ subunit, the combined number (1200 molecules) of all seven σ subunits (46, 50) is more than the total number (600–700 molecules) of core enzyme molecules that are not involved in transcription and thus are available for binding σ (Figure 2, see color insert). The majority of free RNA polymerase molecules in the cytosol should therefore be in the holoenzyme form, associated with one of the σ subunits. These findings support the model that competition takes place between the σ subunits for binding a limited supply of core enzyme. To estimate the relative levels of different holoenzyme forms, two parameters must be determined: the intracellular concentrations of all seven σ subunits and the binding affinity of core enzyme to each σ subunit. The concentration of each σ subunit is subject to variation depending on the cell growth conditions, although the concentration of core enzyme stays constant at a level that is characteristic of the rate of cell growth (38, 43). The first systematic determination of the intracellular concentrations of all seven σ subunits has been performed for the laboratory strain W3110 type-A, which contains the intact forms of both σ S and σ F (47). The results indicate that the intracellular concentration is highest for the σ 70 subunit in both exponential and stationary phases and under various stress conditions (46, 50, 68). In exponential-phase cells, two of the alternative σ subunits, σ N and σ F, are present in significant concentrations, but, in addition, the level of σ S becomes detectable in stationary phase (Figure 1, see color insert). The core-binding affinities have been determined in vitro by measuring the amount of core enzyme-bound σ subunit in the presence of various amounts of

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each σ subunit and a fixed amount of core enzyme (H Maeda, N Fujita, A Ishihama submitted for publication). Among the seven σ subunits from E. coli, σ 70 was found to have the highest affinity to the core enzyme. The affinities of the other six σ subunits ranged downwards by 16-fold from σ 70 (0.26 nM) to σ S, which has the weakest binding activity (4.28 nM) (Figure 2, see color insert). From these two lines of experimental data, we can now estimate the intracellular concentration of each holoenzyme. The numbers of each free holoenzyme formed in an E. coli cell during exponential growth are thus calculated to be 550 molecules of Eσ 70, 95 molecules of Eσ F, and 55 molecules of Eσ N (Figure 2, see color insert).

SIGMA REPLACEMENT DURING GROWTH TRANSITION FROM EXPONENTIAL TO STATIONARY PHASE Bacterial populations in nature often exist in the stationary phase or a state of partial or complete starvation. The term stationary phase is used to denote a fixed physiological state regardless of what factors led to growth cessation. The stationary phase is synonymous with the starvation for only an ideal case in which the limiting nutrient leading to growth cessation can be specified, but even in laboratory culture conditions the mechanism of cell growth cessation usually involves multiple factors. Bacteria are capable of sensing the maximum cell density (or “quorum”) and then can grow under a given condition and communicate this to other members of the same species by production of extracellular signaling molecules. This allows the single-celled prokaryotes to function in some respects as if they are multicellular organisms (55, 86). After entry into stationary phase, a number of genes, that are not expressed during exponential phase are expressed in a sequential manner (reviewed in 41, 42). N-Acyl homoserine lactones are one group of the diffusible extracellular quorum-sensing signaling molecules (bacterial pheromones) that are used for cell-cell communication in some bacteria (88). The synthesis of N-acyl homoserine lactones also arises as a natural response to starvation and entry into stationary phase for E. coli (37), but the role of these molecules has not yet been established for this species. A family of diketopiperazines such as cyclo(1Ala-Val) and cyclo(Pro-Tyr) appear to function as signal molecules in the quorum-sensing systems in certain bacteria (35). Upon entry into stationary phase, a bacterial culture can divide into two populations, one entering into dormant phase (sporulation for gram-positive bacteria) and the other into programmed cell death (or prokaryotic apoptosis) (34, 54). The choice between these fates seems to be under genetic control (e.g. see 101). Mutations in the rpoS gene often confer growth advantage for stationary-phase cultures (47, 104). Phages can express anti-cell death functions to favor their replication in infected cells (18). The total number of detectably expressed genes among the >4000 putative genes on the E. coli genome is <1000 in exponentially growing cells, as estimated from the protein patterns on two-dimensional gel electrophoresis (96). The

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accumulation of extracellular quorum-sensing signals ultimately leads to repression of most of these growth-related genes and, instead, induces the expression of a new set of genes that are specific for survival in the stationary phase. Up to now, ∼100 genes have been identified that are expressed only in stationary phase (27, 41, 42, 64, 65). The precise selection of genes expressed in stationary phase, however, differs depending on the factors that led to cessation of cell growth. This drastic change in gene expression pattern is accompanied by a change in activity and specificity of both the transcription apparatus and the translation machinery (reviewed in 40, 41). The most significant changes are preceded by the appearance of the stationary-phase-specific σ S subunit (for reviews, see 32, 64, 65), which is involved in transcription of most, if not all, of the stationary-phase genes (Table 1). The σ S subunit is maximally expressed at the onset of stationary phase, the maximum level being ∼30% that of σ 70, or 230 molecules per cell (46, 50; Figure 2, see color insert). The onset of σ S synthesis is signaled by changes in metabolism that lead to reductions in growth. Even during the exponential-growth phase, therefore, the synthesis of σ S can be induced when cells are exposed to conditions that are unfavorable for growth, so that, at very slow growth rates, E. coli contains σ S even in exponential phase.

LEVEL AND ACTIVITY CONTROL OF SIGMA-S The synthesis and accumulation of σ S are controlled at multiple levels, including transcription, translation, protein turnover, and activity control (Figure 3, see color insert). Transcription control of rpoS involves a number of factors, including ppGpp and polyphosphate as positive regulators and cyclic AMP (cAMP) and UDP-glucose as negative regulators (reviewed in 64). Upon increase in the concentration of the stringent control signal ppGpp, transcription of rpoS is enhanced (24, 62). ppGpp binds to the β subunit of RNA polymerase (13) and thereby inhibits transcription of stringently controlled genes. However, as for other genes under the positive control of ppGpp such as those for the amino acid biosynthetic operons, the molecular mechanism of transcription activation by ppGpp remains unsolved. The mechanism(s) by which rpoS transcription is stimulated by decreases in the concentrations of the catabolite repression signal cAMP (32, 64) or UDP-glucose (8) also remain unknown. Translation of rpoS messenger RNA (mRNA) is stimulated under various stress conditions by several regulatory factors, including the RNA-binding Hfq (HF-1) protein (10, 11, 73) and the small regulatory DsrA-RNA (63), and is repressed by the histonelike protein H-NS (52). These factors modulate the secondary structure of the ribosome-binding region of rpoS mRNA. Hfq was originally identified as a host factor (HF-1) for phage Qβ replication (23). After gene cloning (51), it was identified as one of the most abundant E. coli proteins associated with both nucleoid and ribosomes (92, 93). Several lines of evidence indicate that Hfq binds a set of mRNAs including rpoS mRNA and regulates the efficiency of their translation by

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TABLE 1 Stationary-phase–specific genes under the control of σ S

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Gene

Gene function

Reference(s)

Genes involved in cell morphology and division bolA Control of PBP6 synthesis cfa Cyclopropane fatty acid synthase csgBA Curly fimbriae formation csgCDEF Curly fimbriae formation fic Cell division control ftsQAZ Septum formation γ-Aminoburytic acid permease gabP hdeAB Periplasmic proteins htrE Pili construction protein osmB Outer membrane lipoprotein osmC Outer membrane lipoprotein osmE Outer membrane lipoprotein osmY Periplasmic protein pqi5 Membrane protein potF (o381) Periplasmic putrescine-binding protein proU Glycine betaine and proline transport proP Glycine betaine and proline permease vanABCDF D-Ala-D-ala dipeptide transport vanX D-Ala-D-ala dipeptidase yhiU Two-membrane drug efflux pump

64, 65 64, 65 64, 65 64, 65 64, 65 65 88a 65 64, 65 64, 65 9a 14a 64, 65 65 88a 83 65 63a 63a 89a

Genes involved in energy metabolism and anabolism acnA Aconitase acs Acetyl-CoA synthetase aldB Aldehyde dehydrogenase cbdAB Cytochrome bd-II oxidase cyxAB Cytochrome oxidase III frd Fumarate reductase galEKT Galactose use glpD Glyacerol-3-phosphate dehydrogenase hmp Flavohemoglobin Hmp hyaABCDEF Hydrogenase I (hydrogen oxidation) nrz NRZ nitrate reductase o371 Glucose dehydrogenase B homolog poxB Pyruvate oxidase (acetate synthesis) tam (o252) trans-Aconitate methyltransferase

15a 89a 65 65 64, 65 65 65 65 65 65 12c 89a 65 12a

Genes involved in protein and nucleic acid breakdown appY Transcription factor for appABC clpA Clp protease subunit wrbA TrpR repressor binding protein xthA Exonuclease III

65 65 65 64, 65 (Continued )

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(Continued )

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Gene

Gene function

Reference (s)

Genes involved in gene regulation, DNA replication, and nucleoid configuration aidB Methylation damage repair of DNA 64, 65 cbpA Curved DNA-binding protein 65 dnaN DNA polymerase III β-subunit 96a dps (pexB) DNA binding protein 64, 65 hip (himD) IHF subunit 65 hns (osmZ) H-NS 65 rob (cbpB) Curved DNA-binding protein 51a rpoS RNA polymerase σ S 91a topA DNA topoisomerase I 65 Genes involved in production of storage products glgCAF Glycogen synthesis glgS Glycogen synthesis otsA (pexA) Trehalose synthesis otsB (perX) Trehalose-6-phosphate phosphatase

65 64, 65 64, 65 64, 65

Genes for stress resistance ahpCF ecp-thtrE cpxRA gadAB gor katE katG ldc oxyR pcm pspABCE sodC sprA treA (osmA) treF usp

Alkyl hydroperoxide reductase Thermotolerance/osmotolerance Disaggregation of misfolded proteins Glutamic acid decarboxylase Glutathione oxidoreductase Catalase HPII Catalase-peroxidase HPI Lysine decarboxylase Transcription factor for oxy regulon L-Isoaspartyl protein methyltransferase Phage shock proteins Periplasmic superoxide dismutase Virulence to animals Periplasmic trehalase Cytoplasmic trehalase Universal stress proteins

70a 88a 16a 12b, 15b 65 64, 65 64, 65 51b 70a 96b 65 25a 29a 64, 65 35a 21a

Carbon starvation-induced proteins

64, 65 89a 89a 89a 65 65 65

Unknown functions csiDEF f186 f 253a o215 pexCDEF yciG yohF

Carbon starvation-induced proteins

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modulating the secondary structure of as-yet-unidentified sites near the translation initiation codon (10, 11, 74). The regulatory RNA encoded by oxyS is known to compete for Hfq and, as a result, inhibits translation of the rpoS mRNA (106). Structural modification of rpoS mRNA can also be mediated through direct RNA-RNA interaction with DsrA RNA (63, 91). DsrA, an 87-nucleotide untranslated RNA, acts as a positive riboregulator of RpoS synthesis (91), by enhancing translation of rpoS mRNA through RNA:RNA interactions with rpoS mRNA (63). DsrA is required for the optimal translation of rpoS mRNA with the help of Hfq (11, 73, 91), and, accordingly, dsrA mutants fail to accumulate σ S in stationary phase. The product of dksA (dnaK suppressor) is also required for the optimal translation of rpoS mRNA, but the region of rpoS mRNA required to see the effects of dsrA mutations was identified on rpoS between codons 8 and 73 (98), suggesting that the contact sequence of DksA is located downstream of the translation initiation site on rpoS mRNA. The histone-like protein H-NS plays a dual role by interfering with both transcription and translation of rpoS (52, 102). The target of H-NS binding on the rpoS mRNA is located upstream from the initiation codon. Thus, DsrA RNA antagonizes the H-NS–mediated inhibition of rpoS mRNA translation. LeuO, however, represses dsrA expression and thereby reduces rpoS translation at low temperature (52). The σ S protein is subject to rapid turnover in exponential-phase E. coli cells. The increase in σ S level in stationary-phase E. coli results, at least in part, from a large increase in the stability of σ S protein (105). The clpP gene product is one protease that is responsible for degradation of σ S (89, 98). The target site for the ClpP protease action apparently resides in a 20-amino-acid stretch near the middle of the σ S protein (89). The σ S factor also becomes stable in rssB mutants because the activity of ClpP protease is enhanced by RssB [or SprE (MviA for Salmonella typhimurium)], a response regulator (73). Phosphorylation of S. typhimurium MviA (RssB/SprE for E. coli) is required for this regulation, but no evidence has been obtained to support the model that acetyl phosphate contributes to the phosphorylation of MviA, although the σ S level increases about fivefold when acetate is used as a carbon source (15). Rss/SprE contains a unique C-terminal output domain and is the first known response regulator involved in the control of protein turnover (73). On the other hand, the ClpP protease is activated by the ClpP-specific chaperone ClpX (26, 97, 99) and inhibited by the general chaperone DnaK (65). LrhA, a LysR homolog, promotes degradation of σ S, indirectly activating the ClpP protease by modulating the activity of RssB/SprE (25). The promoter recognition specificity of Eσ S is not entirely understood because the promoters of the stationary-specific genes so far analyzed do not show any distinctive consensus sequence and are mostly recognized by both Eσ 70 and Eσ S holoenzymes in vitro (53, 94, 95). Several lines of evidence indicate that some additional factors are involved in the control of activity and specificity of these two different forms of RNA polymerase holoenzyme. Under stress conditions, there are marked increases in the intracellular concentrations of compatible solutes, including stress protectants such as potassium glutamate, trehalose, and glycine

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betaine, and of some storage products such as glycogen and polyphosphate (e.g. see 78). These compounds influence the activity and specificity of RNA polymerase to various degrees. The activity of σ S holoenzyme is modulated by glutamate (17, 83) and trehalose (59) at the steps of Eσ S holoenzyme formation and Eσ S holoenzyme binding to certain promoters. Transcription by Eσ S of some osmoregulated genes such as osmB and osmY takes place in the presence of ≥0.5 M concentrations of potassium glutamate, which completely inhibit the activity of Eσ 70 in vitro (17). The optimal concentrations of trehalose for maximal transcription by Eσ 70 and Eσ S are ∼0.5 and 1.0 M, respectively (59). RNA polymerase from stationary-phase cells of E. coli is associated with an acidic compound(s) and exhibits an altered promoter selectivity (77). The RNA polymerase-associated acidic compounds were found to be inorganic polyphosphate (poly P) (60), which is known to accumulate in stationary-phase cells (55). The ubiquitous occurrence of poly P is suggestive of some important physiological role(s) for this polymer, and a number of hypotheses have been proposed for its function (56, 84). Because mutants that are defective in the ppk gene encoding polyphosphate kinase (PPK) are also defective in survival in the stationary phase (60), poly P is now believed to play a role in bacterial adaptation to the stationary phase. At low salt concentrations, poly P inhibits transcription in vitro by both Eσ 70 and Eσ S holoenzymes. Upon increasing the concentration of potassium glutamate, however, poly P inhibition is relieved for the Eσ S holoenzyme, but not for Eσ 70, suggesting that poly P may play a role in the promoter selectivity control of RNA polymerase in E. coli growing under high-osmolarity conditions and in stationary phase (60). The crl gene stimulates transcription of csgBA, the locus encoding the major subunits of curli (the surface structures in stationary phase). crl-null alleles influence the expression of σ S-regulated genes in a fashion similar to an rpoS-null allele. Crl stimulates the activity of the rpoS regulon by stimulating σ S activity during stationary phase (79). The mechanism of σ S activity control by Crl is not yet known.

ACTIVITY CONTROL OF THE SIGMA SUBUNITS BY ANTI-SIGMA FACTORS A new frame of transcription regulation has been discovered, in which the activity of RNA polymerase σ subunit is controlled by so-called anti-σ factors (for a review, see 36). An anti-σ factor is defined by the ability to form a complex with its cognate σ subunit and thereby inhibits the σ function. This definition excludes other σ subunits that compete for available core enzyme. The control of σ activities by anti-σ factors has been well established in Bacillus subtilis (12, 57). Among seven E. coli σ subunits, anti-σ factors have been identified for σ 70, σ F, and σ E (cited in 48). The fliA gene, one of the class II genes within the transcription hierarchy of the flagellar biosynthetic pathway, encodes the flagella-specific RNA polymerase

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σ subunit σ F, which is responsible for transcription of class III genes (30). A negative regulatory gene, flgM, for class III genes encodes anti-σ F factor, which inhibits σ F activity (61). FlgM exists as a binary complex with σ F in the early phase of flagella formation, but it is secreted out of the cell after completion of the flagella hook-basal body, resulting in reactivation of the σ F subunit. The contact site for FlgM on the σ F subunit is located within region 4 (45), as for class II transcription factors (28, 40). Under the steady state of E. coli growth, a large fraction of the σ F subunit stays as a complex with FlgM (48), and thus the actual concentration of Eσ F holoenzyme must be considerably lower than the σ F level. The first member of the extracytoplasmic function subfamily of σ subunit identified in E. coli is σ E, which was originally identified as a factor required for survival on exposure to extremely high temperature (19). Increasing the amounts of outer membrane proteins increases σ E-dependent gene expression, whereas reducing outer membrane proteins results in a decrease in σ E-dependent transcription (69). Overexpression of the dsb genes, coding for proteins involved in disulfide bond formation, and the surA and fkpA genes, coding for distinct peptidyl-prolyl isomerases, can compensate for and/or complement some of σ E mutations (71), indicating that σ E is required for expression of the repair systems of denatured proteins under certain stress conditions. The product of rseA, located downstream of the rpoE gene within the same operon negatively regulates σ E (16, 72). The N terminus of RseA interacts directly with σ E. After screening for proteins that are associated with the σ 70 subunit, Jishage & Ishihama (48) isolated Rsd (regulator of sigma D). Isolated Rsd forms a binary complex with purified σ 70 and thereby inhibits its function. It was therefore proposed that Rsd is an anti-σ 70 factor. Rsd is not present in exponentially growing E. coli cells (48, 49), and in these conditions most of the free RNA polymerase (not engaged in RNA synthesis) must be in the Eσ 70 holoenzyme form, which can be immediately used for transcription of the growth-related genes. On entry into stationary phase, Rsd starts to be synthesized and reaches its maximum level in the early stationary phase (49). As in the case of FglM-σ F interaction, the contact target for Rsd on σ 70 is located within region 4. Together, these observations indicate that, in the stationary-phase E. coli, some of the unused σ 70 subunits are stored in inactive form as a complex with Rsd, the anti-σ 70 factor.

MODULATION OF RNA POLYMERASE SPECIFICITY BY TRANSCRIPTION FACTORS Each holoenzyme recognizes and transcribes a different set of genes, but transcription of some genes requires, in addition, accessory proteins or nucleotide factors. The functional specificity of RNA polymerase holoenzyme is modulated through interaction with 1 or 2 (in some cases) of ∼100–150 different transcription factors. These factors can be classified based on their contact subunit(s)

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on RNA polymerase (40; Figure 4, see color insert). Regulatory proteins were originally classified as activators, or, if they were known to inhibit transcription, as repressors. More recent studies, however, indicate that both activators and repressors can have dual functions, activating or inhibiting transcription from different promoters depending on where they bind to the DNA (e.g. 1, 14, 44). Moreover, both activators and repressors seem to make direct contact with the RNA polymerase to function [both are hereafter referred to simply as transcription factors (40)]. Many stationary-phase genes are transcribed by two different systems, depending on cell growth conditions; one is σ S dependent but transcription factor independent, and the other is σ 70 dependent but transcription factor dependent. Such genes usually carry multiple promoters, to be recognized by each form of the transcription apparatus. It is surprising, however, that the two systems initiate transcription at the same site in some cases. For instance, some carbon catabolite genes such as dps or pexB, encoding stationary-specific DNA-binding protein Dps with regulatory and protective roles, are transcribed by Eσ 70 in cAMPreceptor protein (CRP)–dependent fashion, but can also be transcribed by Eσ S in the absence of cAMP-CRP; thus, the expression of these genes is cAMP-CRP dependent in growing phase, but becomes independent of cAMP-CRP in stationary phase (66). Furthermore, the dps promoter is activated by OxyR when it is transcribed by Eσ 70 during growth, but in the stationary phase it is transcribed by Eσ S without the support of OxyR [integration host factor (IHF) is required instead (2)]. Thus, the same transcriptional start is achieved both by a combination of Eσ 70 with stress-responsive transcription factors and by Eσ S holoenzyme. Other recent evidence substantiates the suggestion that σ S overlaps functionally with σ 70 (53, 94, 95). The RNA polymerase holoenzymes carrying other minor σ subunits such as Eσ N, Eσ H, Eσ F, and Eσ FecI recognize and transcribe genes involved in adaptation to imbalance in nitrogen and other nutrients, in acquisition of heat-shock resistance, in generation of flagella, and in an iron citrate uptake system, respectively. In sharp contrast to the σ S-dependent system, the promoters under the control of these minor σ subunits cannot be recognized by the Eσ 70 holoenzyme, and the holoenzymes containing these minor σ subunits are unable to transcribe σ 70-dependent genes.

FACTORS AFFECTING SELECTIVE UTILIZATION OF TRANSCRIPTION APPARATUS More than 100 promoters have been identified, which can be recognized either in vivo or in vitro by RNA polymerase holoenzyme containing σ S, but no significant consensus sequences have been identified. Instead, a number of σ 70-dependent promoters are transcribed in vitro by the Eσ S holoenzyme (33, 53, 94, 95). One possibility is that the Eσ S holoenzyme recognizes a specific DNA conformation such as bent DNA regions (21). The action of DNA gyrase and the association

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of DNA-binding proteins combine to cause growth-dependent changes in the configuration of the E. coli chromosome, often called the nucleoid, which affect the pattern of gene transcription as well as protecting the genome DNA from stressinduced damage. In agreement with the in vivo findings, transcription in vitro by Eσ S is much higher when directed by templates with low superhelical density (58). The enhancing effect of decreased superhelicity of template DNA on transcription by Eσ S is additive with that of trehalose and potassium glutamate, indicating that the changes in the cytoplasmic composition and the nucleoid conformation independently produce growth-dependent changes in gene transcription. A nucleoid-associated histone-like protein, H-NS, functions as a general silencer for gene transcription, repressing the expression of many and diverse genes (4, 83). Mutations in H-NS can lead to overexpression of stress-induced genes in the absence of stresses. Because the binding of H-NS to target DNA sequences is sensitive to both intracellular potassium glutamate levels (increased after osmotic shock) and the level of DNA superhelicity (decreased during stationary phase), the enhancing effect of high potassium glutamate concentration and low DNA superhelicity on transcription of σ S-dependent genes may be caused not only by activation of Eσ S holoenzyme but also by release from the inhibition by H-NS (17, 83). The protein composition of E. coli nucleoid changes markedly depending on cell growth phase (93). Dps or PexB is a DNA-binding protein that appears in E. coli only in stationary phase and is involved, together with H-NS and IHF, in the condensation of the nucleoid into a more compact configuration. The dps or pexB gene is recognized by Eσ S holoenzyme only when its promoter structure is altered by the binding of another histone-like protein, IHF (2, 66), whose level also increases in stationary phase (5, 93). Both Dps and IHF are required for the efficient expression of σ S-dependent genes required for starvation survival (2, 76). On the other hand, the DNA-binding protein Fis, most abundant in exponential phase (93), generally activates transcription of genes that are highly expressed in exponentially growing cells (9, 75, 107) and represses stationary-specific gene transcription (76, 100). Accordingly, the level of Fis protein changes dramatically upon nutrient upshift, from <100 molecules per cell in stationary phase to >50,000 in exponential phase (6, 93).

MULTIPLE PATHWAYS FOR STATIONARY-PHASE ADAPTATION The highly significant difference in survival levels between rpoS+ and rpoS strains strongly suggests a major role for rpoS (and/or the genes under its control) in stationary-phase survival. E. coli W3110 is an attenuated laboratory strain that has been widely used as a standard for E. coli genetics and as a model strain in the genome program. However, there are at least five independent lineages of strain W3110 that differ in their content of two σ subunits, σ S and σ F (47). Because mutations in the rpoS gene render the wild-type rpoS+ strain nonviable in stationary phase, natural variants lacking the intact σ S must presumably have acquired yet

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unidentified suppressor mutations. Thus, it should be noted that different genetic systems and mechanisms must be present in E. coli for adaptation to stationary phase. In this respect, care should be taken not to draw conclusions from results obtained by using different bacterial strains with different genetic backgrounds.

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CONCLUSION The stationary-phase–associated changes in the pattern of global gene expression in E. coli are mainly mediated by modulation of the specificity of RNA polymerase by replacement of the promoter recognition subunit σ 70 with σ S. Accordingly, the intracellular concentration of σ S increases when cultures stop growing. In addition, the activities of Eσ 70 and Eσ S are regulated in different ways by changes in both the cytoplasmic composition and the conformation of the nucleoid. The overall findings raise the possibility that each stationary-specific promoter carries a specific sequence that is recognized by Eσ S under a specific condition or in the presence of a specific factor. If so, the promoter sequence recognized by Eσ S must vary between groups that require different conditions or factors for function. However, because some E. coli strains lacking σ S can successfully enter stationary phase, alternative pathways must exist, which allow bacterial adaptation to the stationary phase. ACKNOWLEDGMENTS Work at the National Institute of Genetics (NIG) was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, and the CREST fund from the Japanese Science and Technology Corporation. The author thanks his colleagues in NIG and collaborators from 70 laboratories in 20 countries. The author thanks Richard S Hayward for critical reading of the manuscript and helpful comments. Visit the Annual Reviews home page at www.AnnualReviews.org

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Figure 1 Sigma subunits of Escherichia coli. E. coli contains seven species of σ subunit. The RNA polymerase holoenzyme containing each σ subunit recognizes and transcribes a specific set of genes. The intracellular concentrations of all seven σ subunits were determined for both exponential and stationary phases of E. coli W3110 (46, 50, 68).

Figure 2 Intracellular concentration of each holoenzyme form. The intracellular concentrations of all seven σ subunits were determined by quantitative Western blot analysis (46, 50, 68), while the dissociation constant between the σ subunit and the core enzyme was determined by FPLC gel chromatography (Maeda H et al, submitted for publication). The concentrations of all seven holoenzyme forms were calculated from these two values.

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Figure 3 Regulation of the level and activity of σ s subunit. The synthesis of σ s subunit is regulated at both transcription and translation steps by a number of regulatory factors. The metabolic stability of σ s subunit is also controlled. The activity of holoenzyme containing σ s subunit is specifically activated or repressed by a number of stationary-phase specific factors. Transcription of some σ s-dependent genes is modulated by AppY, BolA, CRP, Fis, IHF, Lrp (for a review see 65).

Figure 4 Classification of E. coli transcription factors. Transcription factors have been classified on the basis of the contact subunit of RNA polymerase (40, 42).

Annual Review of Microbiology Volume 54, 2000

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CONTENTS THE LIFE AND TIMES OF A CLINICAL MICROBIOLOGIST, Albert Balows ROLE OF CYTOTOXIC T LYMPHOCYTES IN EPSTEIN-BARR VIRUS-ASSOCIATED DISEASES, Rajiv Khanna, Scott R. Burrows BIOFILM FORMATION AS MICROBIAL DEVELOPMENT, George O'Toole, Heidi B. Kaplan, Roberto Kolter MICROBIOLOGICAL SAFETY OF DRINKING WATER, U. Szewzyk, R. Szewzyk, W. Manz, K.-H. Schleifer THE ADAPTATIVE MECHANISMS OF TRYPANOSOMA BRUCEI FOR STEROL HOMEOSTASIS IN ITS DIFFERENT LIFE-CYCLE ENVIRONMENTS, I. Coppens, P. J. Courtoy THE DEVELOPMENT OF GENETIC TOOLS FOR DISSECTING THE BIOLOGY OF MALARIA PARASITES, Tania F. de Koning-Ward, Chris J. Janse, Andrew P. Waters NUCLEIC ACID TRANSPORT IN PLANT-MICROBE INTERACTIONS: The Molecules That Walk Through the Walls, Tzvi Tzfira, Yoon Rhee, Min-Huei Chen, Talya Kunik, Vitaly Citovsky PHYTOPLASMA: Phytopathogenic Mollicutes, Ing-Ming Lee, Robert E. Davis, Dawn E. Gundersen-Rindal ROOT NODULATION AND INFECTION FACTORS PRODUCED BY RHIZOBIAL BACTERIA, Herman P. Spaink ALGINATE LYASE: Review of Major Sources and Enzyme Characteristics, Structure-Function Analysis, Biological Roles, and Applications, Thiang Yian Wong, Lori A. Preston, Neal L. Schiller INTERIM REPORT ON GENOMICS OF ESCHERICHIA COLI, M. Riley, M. H. Serres ORAL MICROBIAL COMMUNITIES: Biofilms, Interactions, and Genetic Systems, Paul E. Kolenbrander ROLES OF THE GLUTATHIONE- AND THIOREDOXINDEPENDENT REDUCTION SYSTEMS IN THE ESCHERICHIA COLI AND SACCHAROMYCES CEREVISIAE RESPONSES TO OXIDATIVE STRESS, Orna Carmel-Harel, Gisela Storz RECENT DEVELOPMENTS IN MOLECULAR GENETICS OF CANDIDA ALBICANS, Marianne D. De Backer, Paul T. Magee, Jesus Pla FUNCTIONAL MODULATION OF ESCHERICHIA COLI RNA POLYMERASE, Akira Ishihama BACTERIAL VIRULENCE GENE REGULATION: An Evolutionary Perspective, Peggy A. Cotter, Victor J. DiRita LEGIONELLA PNEUMOPHILA PATHOGENESIS: A Fateful Journey from Amoebae to Macrophages, M. S. Swanson, B. K. Hammer THE DISEASE SPECTRUM OF HELICOBACTER PYLORI : The Immunopathogenesis of Gastroduodenal Ulcer and Gastric Cancer, Peter B. Ernst, Benjamin D. Gold PATHOGENICITY ISLANDS AND THE EVOLUTION OF MICROBES, Jörg Hacker, James B. Kaper DNA SEGREGATION IN BACTERIA, Gideon Scott Gordon, Andrew Wright

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POLYPHOSPHATE AND PHOSPHATE PUMP, I. Kulaev, T. Kulakovskaya ASSEMBLY AND FUNCTION OF TYPE III SECRETORY SYSTEMS, Guy R. Cornelis, Frédérique Van Gijsegem PROTEINS SHARED BY THE TRANSCRIPTION AND TRANSLATION MACHINES, Catherine L. Squires, Dmitry Zaporojets

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HOLINS: The Protein Clocks of Bacteriophage Infections, Ing-Nang Wang, David L. Smith, Ry Young OXYGEN RESPIRATION BY DESULFOVIBRIO SPECIES, Heribert Cypionka REGULATION OF CARBON CATABOLISM IN BACILLUS SPECIES, J. Stülke, W. Hillen IRON METABOLISM IN PATHOGENIC BACTERIA, Colin Ratledge, Lynn G Dover

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