Download Eubacterial sigma

FEMS Microbiology Reviews 22 (1998) 127^150
Eubacterial sigma-factors
M.M.S.M. Woësten *
Department of Bacteriology, Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Universiteit Utrecht,
P.O. Box 80.165, 3508 TD Utrecht, The Netherlands
Received 20 November 1997 ; received in revised form 25 June 1998; accepted 30 June 1998
Abstract
The initiation of transcription is the most important step for gene regulation in eubacteria. To initiate transcription, RNA
polymerase has to associate with a small protein, known as a c-factor. The c-factor directs RNA polymerase to a specific class
of promoter sequences. Most bacterial species synthesize several different c-factors that recognize different consensus
sequences. This variety in c-factors provides bacteria with the opportunity to maintain basal gene expression as well as for
regulation of gene expression in response to altered environmental or developmental signals. This review focuses on the
function, regulation and distribution of the 14 different classes of c-factors that are presently known. z 1998 Federation of
European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.
Keywords : Transcription initiation ; Eubacteria ; Sigma-factor; Promoter consensus sequence
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Two families of bacterial c-proteins . . . . . . . . . . . . . . . . . . . . . . .
3. The c70 -family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Group 1. Primary c-factors . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Group 2. The nonessential primary-like c-factors . . . . . . . . .
3.2.1. Subgroup 2.1. Stationary-phase c-factors . . . . . . . . . . .
3.2.2. Subgroup 2.2. Cyanobacterial c-factors . . . . . . . . . . . .
3.2.3. Subgroup 2.3. The c-factors of high-GC Gram-positive
3.3. Group 3. Alternative c-factors . . . . . . . . . . . . . . . . . . . . . . .
3.3.1. Subgroup 3.1. Flagellar c-factors . . . . . . . . . . . . . . . .
3.3.2. Subgroup 3.2. Extracytoplasmic function c-factors . . . .
3.3.3. Subgroup 3.3. Heat shock c-factors . . . . . . . . . . . . . . .
3.3.3.1. Sigma 32 and related c-factors . . . . . . . . . . . .
3.3.3.2. Sigma B and related c-factors . . . . . . . . . . . . .
3.4. Subgroup 3.4. Sigma-factors involved in sporulation . . . . . . .
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* Present address: Washington University, School of Medicine, Department of Molecular Microbiology, 660 S. Euclid Ave. Campus
Box 8230, St. Louis, MO 63110, USA. Tel.: +1 (314) 362 3691; Fax: +1 (314) 362 1232; E-mail: [email protected]
0168-6445 / 98 / $19.00 ß 1998 Federation of European Microbiological Societies. Published by Elsevier Science B.V.
PII: S 0 1 6 8 - 6 4 4 5 ( 9 8 ) 0 0 0 1 1 - 4
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M.M.S.M. Woësten / FEMS Microbiology Reviews 22 (1998) 127^150
3.4.1. Sigma H . . . . . . . . . . . . . . . . . .
3.4.2. Sigma F . . . . . . . . . . . . . . . . . .
3.4.3. Sigma E . . . . . . . . . . . . . . . . . .
3.4.4. Sigma G . . . . . . . . . . . . . . . . . .
3.4.5. Sigma K . . . . . . . . . . . . . . . . . .
4. The c54 -family . . . . . . . . . . . . . . . . . . . . .
5. Factors that a¡ect transcription initiation .
6. Anti-sigma-factors . . . . . . . . . . . . . . . . . . .
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Bacteria encode several thousands of di¡erent proteins, which are necessary for normal cell functions
or for adaptation to environmental changes. These
proteins are not required at the same time or in the
same amount. Regulation of gene expression therefore enables the cell to control the production of
proteins needed for its life cycle or for adaptation
to extracellular changes. This regulation in turn
makes it possible for the bacterium to adequately
adapt to rapid changes in the environment. The various steps during transcription and translation are
therefore subject to di¡erent regulatory mechanisms.
The most prominent step in gene regulation is the
initiation of transcription in which the DNA-dependent RNA polymerase (RNAP) is the key enzyme. Depending on the growth rate, 1500 to
11400 RNAP molecules are present in an Escherichia
coli cell [1]. As calculated by the synthesis of stable
RNA, 24% to 79% of these molecules respectively,
are actually engaged in the synthesis of RNA at any
particular time [1]. The RNAP or the RNAP core
enzyme is the catalytic machinery for the synthesis of
RNA from a DNA template [2]. However, RNAP
cannot initiate transcription by itself. Initiation of
transcription requires an additional polypeptide
known as a c-factor. Sigma-factors are a family of
relatively small proteins that can associate in a reversible way with the RNAP core enzyme. Together,
the c-factor and the RNAP core enzyme form an
initiation-speci¢c enzyme, the RNAP holoenzyme
[3,4].
Initiation of transcription in eubacteria is a multistep process which begins with the binding of RNAP
holoenzyme, containing c70 or a c70 -related c-factor,
to a speci¢c DNA sequence recognized by this en-
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zyme as a promoter [5^7] (Fig. 1). Recognition of a
promoter sequence is directed primarily by the csubunit of the RNAP holoenzyme. The binding of
RNAP holoenzyme to the promoter results in a socalled `closed complex' which is converted into an
`open complex' by melting of a short region of
DNA within the sequence bound by the enzyme. In
the resulting ternary complex, the RNAP holoenzyme starts to produce small 2 to 12 bp RNA molecules, but remains located at the promoter. After
dissociation of the c-subunit, the RNAP core enzyme moves along the DNA, meanwhile synthesizing
the nascent RNA molecule. A locally unwound region of DNA moves with the enzyme. The RNAP
core enzyme and RNA are released when a terminator structure or factor is encountered and the DNA
is then fully restored to duplex condition [7].
The frequency at which the RNAP holoenzyme
initiates transcription, also known as the `strength'
of a promoter, is in£uenced by the promoter sequence and the conformation of the DNA in the
promoter region. The c-factor recognizes two conserved sequences in the promoter region, known as
the promoter consensus sequence [8]. The model proposed in Fig. 1 is supported by footprint analyses in
which c-factor or fragments of c-factor have been
shown to bind speci¢cally to promoter DNA sequences [9^11] and by speci¢c base pair and amino acid
substitutions in the promoter consensus sequences or
c-factor [6,12^15]. Most bacterial species synthesize
several di¡erent c-factors which direct the RNAP
holoenzyme to distinct classes of promoters with a
di¡erent consensus sequence. This variety in c-factors provides the bacterium with the opportunity to
maintain basal gene expression as well as for regulation of gene expression in response to speci¢c environmental stimuli.
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M.M.S.M. Woësten / FEMS Microbiology Reviews 22 (1998) 127^150
129
Fig. 1. Schematic representation of several steps required for the initiation of transcription of RNAP containing c70 or a c70 -related cfactor. The RNAP holoenzyme binds to the promoter to form the closed complex. Conformational changes in the closed complex result
in an open form in which the 310 promoter region is melting out. In this open form the RNAP holoenzyme starts to produce small
RNA molecules. A ternary complex is formed. Finally the RNAP of which the c-factor is dissociated starts to transcribe an mRNA molecule. See text for details.
2. Two families of bacterial c-proteins
Based on sequence similarity, the bacterial c-fac-
tors can be grouped into two families, the c70 - and
c54 -family, with little if any sequence identity between them [16,17]. The majority of the c-factors
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M.M.S.M. Woësten / FEMS Microbiology Reviews 22 (1998) 127^150
Fig. 2. Structure function maps of c70 - and c54 -family of c-factors. Regions shown as a solid box represent the most conserved parts of
the c-factors. A detailed functional assignment for the subregions of the c70 -family proteins is displayed in the expanded view. Region III
of the c54 -family contains three structures indicated as X-link, HTH and the RpoN box. They are involved in DNA binding.
in eubacteria belong to the c70 -family. This family is
named after the 70 kDa primary c-factor from E.
coli [18]. All eubacteria contain one or more c-factors belonging to the c70 -family, which is divided
into several structurally and functionally related
(sub)groups. Many eubacteria also contain a c-factor which belongs to the c54 -family [19], named for
the 54 kDa nitrogen regulation c-factor of E. coli.
The c54 -family contains only one group of c-factors
which are not essential for certain growth conditions.
The identi¢cation of c-factors in various bacterial
species has led to similar c-factors having di¡erent
names and even di¡erent c-factors having identical
names.
3. The c70-family
Sequence comparison of c70 -family proteins from
di¡erent eubacteria led to the identi¢cation of four
highly conserved amino acid regions [20]. As additional sequence data became available these regions
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have been subdivided further [18] (Fig. 2). The Nterminal region or region 1, is the least conserved.
Subregion 1.1 is found only in the primary c-factors
(c70 ) in which it modulates DNA binding and is,
once the closed complex has been formed, important
for the e¤cient initiation of transcription [21]. Subregion 1.2 is probably required for open complex
formation [21]. Deleting region 1.2 prevents RNAP
from progressing beyond the closed complex. This
subregion is found in all c-factors in this family,
except for the extra cytoplasmic function c-factors.
Region 2 is the most conserved region and can be
divided in four subregions. Region 2.1 is important
for interaction with the subunits of core RNAP,
while region 2.3 is involved in DNA melting. Important for DNA binding is subregion 2.4 which has
been implicated in the recognition of the 310 promoter element, a region located approximately 10
nucleotides upstream of the start point of transcription (+1) [8]. Mutations in region 2.4 alter the speci¢c interaction with the 310 promoter element
[12,22,23]. Recently, region 2.5 was identi¢ed as
being involved in contacting nucleotides at positions
314 and 315 in E. coli promoters [24], known in
Bacillus subtilis as the 316 promoter consensus sequence [25]. Regions 3 and 4 are divided in two
subregions. Subregion 3.1 contains a helix-turn-helix
DNA-binding motif and the less conserved region
3.2 may be involved in binding the RNAP core enzyme [18,26]. Region 3.2 is not present in the c-factors K and H. Subregion 4.1 has been proposed to
bind certain transcriptional activators during the initiation of transcription [27,28]. Subregion 4.2 also
recognizes the promoter sequence as mutations in
this region a¡ect the ability of the RNAP holoenzyme to recognize a promoter element approximately
335 nucleotides relative to the start point of transcription [8,12,13,29].
î crystal structure of a fragment of E. coli
The 2.6 A
70
c comprising amino acid 114 to 448 was solved
recently [30]. This fragment contains a part of region
1.2, the complete regions 2.1, 2.2, 2.3, and all but the
C-terminal ¢ve residues of region 2.4. The crystal
structure indicates that all the conserved regions
are closely associated with one another and that region 1.2 stabilizes the fold of the other regions. Residues involved in core RNAP binding lie on one face
of the structure. On the opposite face are residues
131
that interact with the 310 region and residues involved in promoter melting.
The c70 -protein family can be divided into three
di¡erent functionally and structurally related groups
[18] (Fig. 3, Table 1). Group 1 comprises the primary
c-factors responsible for the transcription of most
genes expressed in exponentially growing cells of
which the majority are essential for cell survival.
Group 2 comprises the c-factors which are quite
similar to the primary c-factors in sequence but are
nonessential for cell growth. The third group consists
of the so-called alternative c-factors. These c-factors
di¡er considerably in amino acid sequence from the
primary c-factors and control the transcription of
speci¢c regulons. The three groups of the c70 -family
and the various subgroups are described below.
3.1. Group 1. Primary c-factors
Group 1 is composed of the primary c-factors
present in all known eubacteria [31]. They are responsible for the transcription of most genes expressed in exponentially growing cells and are essential for cell survival. Recent data suggest that there is
only one primary c-factor present in any given eubacterial species [31]. The primary c-factor in E. coli
is encoded by the rpoD gene and is known as c70
[20]. In Mycobacterium spp. this c-factor is known as
MysA, in Streptomyces spp. as HrdB and in B. subtilis and other Gram-positive bacteria as SigA or cA
[31]. The promoter consensus sequence recognized by
the primary c-factor in E. coli and B. subtilis is
found to be similar in many other eubacteria
[32,33]. This promoter sequence is characterized by
two stretches of six nucleotides, TTGACA and TATAAT, centered around positions 335 and 310 respectively, from the transcription start site (+1) (Table 2). A dinucleotide TG at positions 315 and 314
is also conserved in promoters of Gram-positive bacteria but less conserved in E. coli promoters [25,33].
The hexamer sequences around 335 and 310 are
most often separated by a stretch of 16 to 18 nonconserved nucleotides called the spacer. Deviations
from the consensus sequences usually result in reduced promoter activity [25,34,35]. However, certain
prokaryotic promoters can function in the absence of
a 335 promoter element if they have an `extended
310' promoter element, TGnTATAAT [36,37]. The
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Fig. 3. Phylogenetic relationship of the c-factors of the c70 -family. The tree was generated by the program Fitch of the Phylip package
version 3.5c [205] using a PAM matrix-based distance correction from a multiple sequence alignment made be the program Multalin version 4.0 [206]. The scale bar represents 0.2 substitution per site. The sequences used in the alignment were translated from the Genbank
entries given in parentheses: Escherichia coli RpoE (P34086), KatF (X16400), RpoH (M20668), FliA (L36677), RpoD (U23083); Salmonella typhimurium RpoE (P34086), RpoS (U05011) ; Streptomyces aureofaciens HrdE (M90412), HrdA (M90410); Haemophilus in£uenzae
RpoE (P44790); Photobacterium sp. strain SS9 (L41688); Pseudomonas aeruginosa AlgU (U49151), RpoS (D26134); Mycobacterium tuberculosis RpoE (Z95120), SigE (U87242), SigF (Z92771); Myxococcus xanthus CarQ (X71062), SigB (X55500), RpoD (U20669), SigC
(L12992); Synechocystis sp. strain PCC6803 RpoE (D90906), SigF (D90906) ; Bacillus megaterium SigH (X59070) ; Yersinia enterocolitica
FliA (L33466), RpoS (U22043); Bacillus subtilis SigH (M29693), SigF (M15744), SigA (M10089), SigB (M34995), SigE (p06222), SigK
(M15744), SigG (X57547), RpoD (M20144); Clostridium acetobutylium SigG (U07420), SigE (Z23079), SigK (L23317); Steptomyces coelicolor HrdB (X52983), HrdC (P18184), SigF (L11648); Stigmatella aurantiaca SigB (Z14970); Rhodobacter capsulatus RpoD (Z68306); Proteus mirabilis RpoH (D50830); Agrobacterium tumefaciens RpoD (P33452) ; Streptomyces griseocarneus WhiG (X68709) ; Vibrio parahaemolyticus LafS (U52957); Mycobacterium smegmatis MysB (U09863), MysA (U09821) ; Caulobacter crescentus RpoD (U35138), RpoH
(U39791); Synechococcus sp. strain PCC7002 SigA (U15574), SigE (U82485); Anabaena sp. strain PCC7120 SigA (M60046), SigC
(M95759), SigB (M95760) ; Corynebacterium glutamicum SigB (Z49824); Erwinia carotovora RpoS (U66542); Legionella pneumophila FliA
(X98892) ; Vibrio cholerae RpoH (U44432).
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3.4.2. Sigma F
3.4.3. Sigma E
3.4.4. Sigma G
3.4.5. Sigma K
4. The c54 -family
3.3. Heat shock c-factors
3.3.1. Sigma 32 and related
c-factors
3.3.2. Sigma B and related
c-factors
3.4. Sporulation c-factors
3.4.1. Sigma H
3.2. ECF c-factor
Mycobacteria, MysB ; Corynebacteria, SigB;
Streptomyces, HrdA, HrdC-E
2.3. The c-factors of
high-GC Gram-positive bacteria
3. Alternative c-factors
3.1. Flagella c-factor
Transcription of early sporulation and postexponential-growth-phase genes
Transcription of early forespore genes
Transcription of early mother-cell genes
Transcription of late forespore genes
Transcription of late mother-cell genes
Expression of genes involved in: nitrogen
¢xation, nitrate utilization, glutamine
synthetase, dicarboxylate transport, xylene
degradation, ¢mbriae and £agellar synthesis
or levanase production
Bacillus, Clostridium, cH
Bacillus, Clostridium, cF
Bacillus, Clostridium, cE
Bacillus, Clostridium, cG
Bacillus, Clostridium, cK
Rhizobium, Rhodobacter, Pseudomonas,
Bacillus, Caulobacter, Enterobacteriaceae
Expression of genes during stress, fruiting
body formation or maturation of myxospores
Expression of genes during stress or late
sporulation
Expresion of chemotaxis, late £agellar or
early sporulation genes
Expression of genes involved in alginate
biosynthesis, iron uptake, carotenoid biosynthesis, antibiotic production, induction of
virulence factors, resistants to cobalt and
nickel, outer membrane proteins or survival
of high temperature
Major sigma-factor during entry into
stationary phase. Global regulator of gene
expression in cells exposed to hyperosmotic
or acid stress
Controlling gene expression during circadian
responses, carbon and nitrogen availability
or post-exponential-growth phase
Unknown
Major sigma-factor in exponential growing
cells regulates house keeping genes
Functions
Gram-negative bacteria, c32 ; M. xanthus, SigB;
S. aurantiaca, SigC
B. subtilis, Stapylococcus, cB ; Mycobacteria,
Streptomyces, SigF
Enterobacteria, c28 ; Streptomyces, WhiG;
Bacillus subtilis, cD
Pseudomonas aeruginosa, AlgU; Escherichia coli, FecI;
Pseudomonas £uorescens, PbrA; Myxococcus xanthus,
CarQ ; S. coelicolor, E. coli, Mycobacteria, cE ;
Pseudomonas Syringae, HprL ; Alcaligenes eutrophus,
CrnH ; B. subtilis, SigV-Z
Synechococcus, Synechocystis, Anabaena,
SigB-E
Enterobacteria, Pseudomonas, RpoS
2.2. Cyanobacterial c-factors
2. Nonessential primary-like
c-factors
2.1. Stationary phase c-factor
Gram-negative bacteria, c ; Gram-positive bacteria,
cA ; Mycobacteria, MysA; Streptomyces, HrdB
1. Primary c-factors
70
Organism, name c-factor
Group
Table 1
Functions and distribution of the various eubacterial c-factors
[79,129]
[79,129]
[79,129]
[79,129]
[19]
[79,129]
[78,120,121]
[76,108,14]
[75]
[74,87]
[31]
[31,65]
[43]
[31]
Reference
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so-called `extended 310' promoter provides a very
strong recognition signal for the c70 -subunit which
can overcome both the lack of a 335 promoter element as well as less conserved 310 region [38].
Recognition of the 310 and 335 region of the
primary c promoter has been studied extensively
by site-speci¢c mutagenesis. Amino acid substitution
studies within region 2.4 (Fig. 2) of c70 of E. coli
showed that two amino acids at positions 437 and
440 interact with the 310 region of c70 promoters.
These amino acids, glutamine at position 437 and
threonine at position 440, are in contact with the
T/A base pair at position 312 of the 310 promoter
element [12,22,39]. Mutagenesis studies within region
4.2 have shown that the arginine residues at positions 588 and 584 of c70 , respectively, interact with
the G and C residues of the 335 region TTGACA
[12].
tain c-factors which belong to group 2 [31]. The
Enterobacteriaceae and Pseudomonas contain a
group 2 c-factor, known as the stationary-phase-speci¢c c-factor, cS or RpoS [40]. All cyanobacterial
group 2 c-factors are closely related based on amino
acid sequences, but di¡er from the primary c-factors
of the corresponding organisms (Fig. 3). The group 2
c-factors from Gram-positive bacteria with a highGC content do not form such a tight grouping. The
high-GC content Gram-positive bacteria, cyanobacteria and Chloro£exus aurantiacus are the only organisms in which multiple group 2 c-factors have
been found [31]. The subgroups of group 2 are described below.
3.2.1. Subgroup 2.1. Stationary-phase c-factors
In their natural environment, bacteria frequently
experience nutrient limitation and a variety of physical and chemical stresses. Consequently, they endure
and survive long periods without growth [41]. To
survive environmental stress some bacteria produce
highly resistant spores while others enter into the
stationary-growth phase [41,42]. Entry into the stationary phase is characterized by the synthesis of
stress proteins [41]. In E. coli and other enteric bacteria the general stress response is mediated by cS
(RpoS, c38 ) encoded by the rpoS gene [43]. In less
closely related bacteria only the Pseudomonas spp.
3.2. Group 2. The nonessential primary-like c-factors
The c-factors in this group are nonessential for
exponential cell growth [18]. They are highly similar
to the primary c-factors in the amino acid sequence
of their DNA-binding regions, which suggests that
both groups of c-factors recognize similar promoter
sequences. The enterobacteria, the high-GC content
Gram-positive bacteria and the cyanobacteria conTable 2
Consensus sequences recognized by various eubacterial c-factors
c70 -family
Namea
Primary c-factors
Nonessential primary-like c-factors
2.1. Stationary-phase c-factor
Alternative c-factors
3.1. Flagella c-factors
3.2. ECF c-factors
3.3. Heat shock c-factors
c70 , RpoD, SigA
3.4. Sporulation c-factors
c54 -family
a
b
Consensus sequenceb
Reference
335
Spacer
310
TTGACA
16^18
TATAAT
[8,33]
CTATACT
[58]
c38 , RpoS
c28 , FliA, SigD
cE , SigE
c32 , RpoH
cB , SigB
cH , SpoOH
cF , SpoIIAC
cE , SpoIIGB
cG , SpoIIIG
cK , SpoIIIC
TAAA
GAACTT
CTTGAAA
GTTTAA
AGGAWWT
WGCATA
GKCATATT
TGAATA
AC
324
15
16^17
11^16
12^14
12^14
14^15
13^15
17^18
16^17
GCCGATAA
TCTRA
CCCATnT
GGGTAT
RGAAT
GGnRAYAMTW
CATACAMT
CATACTA
CATAnAnTA
312
[74]
[75,89,104,105]
[107]
[78]
[139]
[129,144]
[154,155]
[159]
[167]
cN , RpoN, SigL
TGGCAC
5
TTGCW
[19]
Only the c-factor names for which a consensus recognition sequence has been derived are indicated.
Ambiguous codes: N, any base; R, A or G; W, A or T ; Y, C or T; M, A or C; K, G or T.
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135
have been shown to contain a rpoS-like gene [31,43].
While cS is best known for its crucial role in gene
regulation during entry into stationary phase [41], it
also serves as a global regulator of gene expression in
cells exposed to hyperosmotic [44] or acid stress [45].
Genes regulated by cS encode a variety of di¡erent
functions being involved in the prevention and repair
of DNA damage, cell morphology, modulation of
virulence genes, osmoprotection, thermotolerance,
glycogen synthesis, membrane and cell envelope
functions [43]. Increased expression of stationaryphase RpoS-regulated genes requires an increase in
the abundance of cS . The cellular concentration of
cS in E. coli is controlled at the levels of transcription, translation and protein stability. In E. coli cS is
controlled by four di¡erent c70 promoters of which
the second promoter (P2) in vitro is also recognized
by c38 [46]. The RNA-binding protein HF-1 is essential for the translational regulation of rpoS [47]. Other factors such as DNA-binding protein H-NS [48],
cyclic AMP [49] and UDP-glucose [50] negatively
in£uence production of cS , while pppGpp [51], homoserine lactone [52] and DnaK [53] raise the level
of cS . In exponentially growing cells, cS is very unstable. Involved in the degradation of cS are the
negative regulator RssB and ClpXP protease [54];
mutations in these genes give rise to stable cS . The
decreased proteolytic turnover of cS during acid
shock in S. typhimurium is mediated by MviA [55].
Some promoters that are recognized by cS are also
under the control of c70 [56,57]. Comparison of 33
cS -regulated promoters revealed that the cS promoter consensus sequence lacks a 335 region, but
contains a conserved 310 promoter element, CTATACT [58] (Table 2). The lack of a 335 region is
possibly compensated by a region upstream of the
310 region with an intrinsic DNA curvature [58].
However, the presence of DNA-bending regions is
often found in front of strong promoters [59], and
they are not essential for recognition by cS in vitro
[60]. So far, no DNA-binding protein that acts speci¢cally as an activator of cS -dependent genes has
been identi¢ed [61].
rhythms [62]. The cyanobacterial group 2 c-factors
form a tight cluster of related sequences [31] (Fig. 3).
Members of this cluster are the SigB and SigC cfactors of Anabaena sp., and Synechocystis sp. and
the SigB-E c-factors of Synechococcus sp. [31]. Recent investigations have shown that SigB (RpoD2) of
Synechococcus sp. controls gene expression during
circadian responses [31,63]. Mutagenesis of the
rpoD2 gene resulted in a rhythmic mutant with a
low amplitude phenotype. The sigB and sigC genes
of Anabaena sp. are expressed under nitrogen-limiting conditions but neither of these genes is required
for nitrogen ¢xation or heterocyst di¡erentiation
[64]. The homologues of SigB and SigC in Synechococcus sp. play a role in carbon and nitrogen availability [65]. The sigB increases signi¢cantly when
cells are starved for nitrogen and carbon. Mutation
of sigC increases transcription of sigB indicating that
their functions are related to one another. SigE of
Synechococcus sp. may play a role in the transcription of genes during post-exponential growth in this
organism and therefore, SigE may be similar in function although its sequence places it outside the RpoS
family of c-factors [66].
3.2.2. Subgroup 2.2. Cyanobacterial c-factors
The Gram-negative cyanobacteria are capable of
photosynthetic growth. They are the simplest unicellular organisms known to exhibit circadian (daily)
The third group of the c70 -family comprises alternative c-factors that control the transcription of speci¢c regulons during special physiological or developmental conditions [6,20]. In alignment studies,
3.2.3. Subgroup 2.3. The c-factors of high-GC
Gram-positive bacteria
The c-factors belonging to this group are the
hrdA, hrdC, hrdD and hrdE genes of Streptomyces
spp., mysB of Mycobacterium spp. and sigB of Corynebacterium glutamicum. The c-factors of these
phylogenetically related bacteria are more diverse
than those of the cS and cyanobacterial group 2 cfamily [31] (Fig. 3). The Streptomyces coelicolor hrdD
gene is expressed in exponentially growing cells
and chrdD recognizes the promoters in front of
redD and actII-orf4, two regulatory genes required
for the synthesis of antibiotics [67,68]. Although the
other genes are expressed and can be disrupted, the
functions of these nonessential c-factors remain
unclear [69^73].
3.3. Group 3. Alternative c-factors
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subgroups of the alternative c-factors were found
to cluster together and subsequently shown to have
related functions (Fig. 3, Table 1). This group includes the £agellar [74], extracytoplasmic functional
[75], heat shock [76^78] and the sporulation [79] cfactors.
3.3.1. Subgroup 3.1. Flagellar c-factors
Many motile bacteria possess an external organelle, the £agellum, that propels the cell in directions
dictated by diverse sensory signals. More than 50
genes, which are divided into three classes, are involved in the formation of a functional £agellum in
E. coli and S. typhimurium [80]. At the top of the
£agellar gene hierarchy are the class 1 genes £hD and
£hC of which the products positively control the
transcription of the class 2 genes. Class 2 genes encode components needed in the early stage of basalbody construction, FlgM and c-factor FliA. FliA or
c28 is needed for the expression of class 3 £agellar
proteins involved in the ¢lament assembly and genes
involved in chemotaxis gene hierarchy in various enterobacteria [74,80,81]. FliA is negatively regulated
by FlgM, which binds to c28 until the basal-body
hook formation is completed [82]. The cD of B. subtilis [83] and WhiG of Streptomyces spp. [84,85] are
also members of the £agellar c-factors. The function
and regulation of cD of B. subtilis is similar to that
of FliA of the enterobacteria [86]. WhiG of the
Gram-positive mycelial S. coelicolor is similar in
structure but has a totally di¡erent function compared to FliA. These bacteria can form spores in
the aerial hyphae, a process in which WhiG plays
an essential role [87]. In the absence of WhiG the
aerial hyphae fail to develop sporulation septa, while
an excess of WhiG causes hyper-sporulation [85].
Although WhiG has a totally di¡erent function, the
S. coelicolor whiG gene can complement a £iA null
mutant of S. typhimurium to restore £agellar biosynthesis and motility [87]. Genetic experiments have
shown that WhiG is also regulated post-translationally by FlgM when introduced into S. typhimurium
[87]. It is therefore likely that the WhiG recognizes
the same promoter sequence as FliA of S. typhimurium. Analysis of c28 - and cD -dependent promoters
in E. coli and B. subtilis revealed that RNAP containing c28 or cD recognizes the 335 promoter element, TAAA, and the 310 sequence, GCCGATAA,
separated by a spacer of 15 nucleotides [74] (Table
2).
3.3.2. Subgroup 3.2. Extracytoplasmic function
c-factors
The extracytoplasmic function (ECF) c-subgroup
of the c70 -family is a class of environmentally responsive transcriptional regulators [75]. The amino
acid sequences of these c-factors were so di¡erent
from the c70 -factors that they were initially not recognized as c-factors (Fig. 3). They share similarity
with the primary c-factors in three of the four conserved regions but lack most of region 1 (Fig. 2) [75].
Several bacterial species contain members of the
ECF family in which they control a variety of functions in response to speci¢c extracellular environmental signals. ECF factors include AlgU, which
regulates alginate biosynthesis in Pseudomonas aeruginosa [88,89]. Alginate is a viscous exopolysaccharide believed to protect the bacterium from the adverse environment of the cystic ¢brosis lung [90].
FecI of E. coli [91] and PbrA of Pseudomonas £uorescens [92] are both involved in iron uptake. They
coordinate gene response in low-iron conditions and
are both negatively regulated by the Fur repressor
[92]. The light inducible biosynthesis of carotenoid
in Myxococcus xanthus is controlled by CarQ [93].
Carotenoids are often found in non-photosynthetic
bacteria as light-protective agents [93]. The S. coelicolor cE promotes transcription of a gene encoding
an extracellular agar-degrading enzyme, agarase [75],
while cE of Streptomyces antibioticus is required for
the production of the antibiotic actinomycin [94].
HprL of Pseudomonas syringae controls transcription
and secretion of a plant virulence factor and is inducible by plant extracts [95]. CnrH plays a role in
resistance to nickel and cobalt e¥ux in Alcaligenes
eutrophus [96]. The Mycobacterium smegmatis ECF
c-factor plays a role in the ability to withstand a
variety of stresses [97]. The expression of several outer membrane proteins in the deep-sea bacterium
Photobacterium sp. strain SS9 is regulated by cE in
response to growth under hydrostatic pressure [98].
B. subtilis contains ¢ve ECF c-factors SigV, SigW,
SigX, SigY and SigZ [99,100]. SigX is required for
survival at high temperatures [101] but the function
of the other ECF c-factors is unknown. The second
ECF c-factor of E. coli, cE , is induced not only by
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heat or ethanol but also by disruption of protein
folding in the periplasm [102]. Like FliA of S. typhimurium, the P. aeruginosa AlgU, M. xanthus CarQ
and E. coli cE are negatively regulated by proteins
that bind to the c-factor until the speci¢c activity of
the ECF c-factor is needed [90,102,103].
In spite of the fact that the members of the ECF
subfamily are divergent in amino acid sequence, E.
coli, P. aeruginosa, S. coelicolor and M. xanthus ECF
c-factors recognize the same promoter sequence
[75,89,104,105]. In this promoter sequence, separated
by a spacer of 16 or 17 base pairs, a 335 region,
GAACTT and a 310 region, TCTRA, can be identi¢ed (Table 2). The degree of similarity is higher in
the 335 region than in the 310 region. The B. subtilis sigX gene can complement an E. coli fecI mutant
indicating that the cX recognizes the same promoter
sequence as E. coli FecI [106].
3.3.3. Subgroup 3.3. Heat shock c-factors
When bacteria are exposed to high temperatures
or other environmental stresses, such as ethanol,
heavy metals or hydrogen peroxide, they respond
rapidly with the synthesis of heat shock proteins
[107]. These proteins appear to operate in the prevention and repair of protein damage caused by denaturation and aggregation [77]. In E. coli, the heat
shock response is mediated by the positive regulator
protein c32 [76]. In B. subtilis three classes of heat
shock inducible proteins are known [78] of which the
majority belong to class II which are regulated by cB
[78]. Class II proteins are not only induced by heat
but also by other stresses. Therefore, cB is known as
the general stress-response c-factor in B. subtilis.
3.3.3.1. Sigma 32 and related c-factors. The heat
shock gene response in E. coli and several other
Gram-negative bacteria is mediated by c32
[76,108,109] which is encoded by the rpoH gene. In
E. coli and other Q-proteobacteria, transcription of
the rpoH gene is mediated by c70 and a second
heat shock c-factor, cE [108]. At temperatures above
50³C, the rpoH of E. coli is regulated by cE only
[110]. In Caulobacter crecentus, a member of the Kproteobacteria, the rpoH gene is transcribed from a
c70 promoter and is positively autoregulated by a c32
promoter [111]. In the best characterized heat shock
gene regulatory mechanism, that of E. coli, the cellular concentrations of c32 increase during temper-
137
ature upshift by increasing c32 synthesis and stability. Normally the concentration of c32 is low because
of its half-life of less than 1 min. This instability is
due to the interaction of DnaK with c32 . The resulting complex is degraded by FtsH, a membrane
bound metalloprotease [112]. After temperature upshift DnaK is released from c32 because DnaK preferentially binds to denatured proteins accumulating
during stress [113]. The levels of c32 increase 20-fold,
resulting in increased initiation of transcription from
c32 -dependent promoters. Some of the heat shock
proteins (e.g. GroEL and DnaK) function as molecular chaperones and support proper folding of cellular proteins, while others have protease activity and
degrade incorrectly folded proteins [107]. After the
heat shock proteins have refolded or degraded the
damaged proteins the amount of c32 drops rapidly
because DnaK binds again to c32 [113].
Most bacteria contain only one rpoH gene, except
Bradyrhizobium japonicum which possesses three different rpoH genes [109] of which rpoH2 is essential
for the synthesis of cellular proteins and is not induced by heat shock [109]. The Gram-negative gliding bacteria M. xanthus and Stigmatella aurantiaca
possess two c-factors, SigB and SigC, which are
closely related to the c32 -proteins [114^116]
(Fig. 3). These bacteria migrate to aggregation centers under conditions of nutrient limitation where
they form multicellular structures called fruiting
bodies [117]. During development a small percentage
of the cells in the fruiting bodies di¡erentiates into
spherical myxospores. These spores withstand
prolonged periods of nutrient deprivation. SigC
may play a role in expression of genes involved
in the negative regulation of the initiation of fruiting body formation [116]. SigB is required for the
expression of certain late-stage developmental
genes and for proper maturation of myxospores
[114,115].
In E. coli, 18 c32 -depending promoters have been
identi¢ed. The nucleotide sequences of these promoters were aligned to identify a c32 promoter consensus sequence [107]. This c32 heat shock promoter
consensus sequence di¡ers from that of c70 -dependent promoters, with respect to the 335 consensus
sequence (CTTGAAA), the 310 consensus sequence
(CCCATnT) and the length of the spacer, which is
11 to 16 nucleotides (Table 2). In the K subdivisions
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of the proteobacteria the c32 promoter consensus
sequence seems to be less conserved [118]. Based
on nine promoter sequences, a c32 consensus sequence for these bacteria was derived which shows
a 335 region, CTTG, and a 310 region, CYTATnTnnG, separated by 17 or 18 bp.
3.3.3.2. Sigma B and related c-factors. The sigB
gene product is the general c-factor involved in the
stress response in B. subtilis [78]. Homologous cB factors have been found in Staphylococcus aureus
[119], Mycobacterium spp. [120], and Streptomyces
spp. [121], in the latter two this c-factor is called
SigF (Fig. 3). The function of SigB is similar to
that of RpoS, the general stress c-factor of E. coli
[78,122]. Expression of sigB is activated by heat, alcohol or osmotic stress, but is also activated by the
entry of B. subtilis into the stationary phase in rich
medium or by depletion of glucose, phosphate or
oxygen [78]. Under starvation conditions, SigB is
negatively regulated by the anti-sigma-factor
RsbW. In cells containing a high level of ATP,
RsbW is bound to SigB, preventing transcription
of SigB-dependent promoters. SigB is released from
RsbW when the ATP level drops under starvation
conditions [123]. RsbX is the negative regulator of
SigB under stress induced conditions, in which RsbU
is involved which releases RsbW from SigB [78]. The
sigB gene is transcribed from a cA promoter. However, it is also autoregulated in response to stress or
starvation by a cB promoter [124]. More than 40
general stress proteins are regulated by cB , which
together provide adaptation to stress and starvation
[125]. The SigF of Mycobacterium tuberculosis is similar in function to the SigB of B. subtilis. This stationary-phase or stress-response c-factor is induced
during stationary phase, nitrogen depletion, oxidative stress, alcohol or cold shock [120]. The amino
acid sequence of S. coelicolor SigF is similar to that
of B. subtilis cB gene product (Fig. 3), however, their
functions di¡er. The S. coelicolor sigF encodes a latestage, sporulation-speci¢c c-factor. Knockout mutants of S. coelicolor sigF are unable to sporulate
e¡ectively and produce deformed thin-walled spores
[121]. The S. coelicolor SigF recognizes the B. subtilis
ctc cB promoter in vitro, indicating that cB and SigF
recognize the same promoter sequences [126]. Analysis of eight cB -dependent promoters of B. subtilis
revealed a highly conserved 335 region, GTTTAA,
and a 310 region, GGGTAT, separated by a spacer
of 12 to 14 nucleotides [78] (Table 2).
3.4. Subgroup 3.4. Sigma-factors involved in
sporulation
In response to adverse conditions most bacterial
species undergo physiological changes during which
the whole cell is transformed into a stress-resistant
state with highly reduced metabolic activity. Some
bacteria however, such as the Gram-positive genera
Bacillus, Clostridium and mycelial Streptomyces differentiate into highly resistant spores. This e¡ectively
protects their genome from an otherwise inevitable
fatal end, when living conditions become intolerable.
The sporulation process in Bacillus spp. and Clostridium spp. take place within a sporangium, a structure consisting of two unequal cellular compartments
called the forespore and the mother cell [127]. Sporulation in Bacillus spp. is induced by high cell density
and nutrient limitation [42,128], whereas in Clostridium spp. it is induced by cessation of growth due to
excess carbon and nitrogen source or to exposure to
oxygen [129].
Spore formation in Bacillus spp. is controlled by a
complex regulatory network which involves ¢ve cfactors: cH , the mother-cell-speci¢c cE - and cK -factors and the forespore-speci¢c factors cF and cG .
After the initial commitment to sporulation, in which
cH is involved, the other c-factors are sequentially
activated and e¡ect the sequential expression of a
variety of proteins necessary for the complex task
of spore assembly [79,130]. The Gram-positive mycelial bacteria Streptomycetes are distant relatives of
Bacillus spp. that undergo a quite di¡erent sporulation process [131]. When nutrients become limiting,
an aerial mycelium is formed of which the polyploid
tip compartments become subdivided into haploid
prespore compartments. The prespore compartments
undergo further maturation to give rise to chains of
50 or more spores. The c-factors WhiG and SigF are
required for sporulation in the aerial hyphae of S.
coelicolor [87]. WhiG plays a crucial role in triggering the initiation of sporulation. It activates the early
sporulation whi genes of which the translated proteins together with WhiG itself are necessary for
the transcription of sigF. SigF controls the last stage
of Streptomyces di¡erentiation the spore maturation.
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Based on amino acid sequence, WhiG belongs to the
£agellar c-factors and SigF shows the highest similarity with cB of B. subtilis.
3.4.1. Sigma H
Sigma-factor H is encoded by sigH (or spoOH)
present in B. subtilis and Clostridium spp. [129]. Sigma H is essential for sporulation in B. subtilis and is
the earliest acting developmental c-factor in the
sporulation process [132]. The early sporulation
genes spoOA, spoOF and kinA [133] and the later
acting spoIIA and spoVG genes [134] are transcribed
due to the presence of cH . Sigma H is not only involved in sporulation. It also controls the increase in
post-exponential-growth-phase expression of cA
[135], citG which encodes fumarase, and the ftsAZ
and minCD cell-division operons [136,137]. Sigma H
is present in vegetative cells but its level is increased
when B. subtilis enters the mid-logarithmic-growth
stage [132]. Transcription initiation of sigH is under
negative control of regulator AbrB [132]. The abrB
gene expression is repressed by phosphorylated
SpoOA, which is activated by signals that promote
sporulation [138].
Using eight known cH -regulated promoter sequences for a sequence alignment, a promoter consensus
sequence was derived which contains a 335 region,
AGGAWWT, and a 310 region RGAAT, separated
by a spacer of 12 to 14 bp [139] (Table 2). Studies
with mutants have shown that amino acids at position 96 and 100 of cH interact with the nucleotide G
at position 312 of the nucleotide stretch RGAAT
[23,140].
3.4.2. Sigma F
Sigma-factor F is encoded by sigF or spoIIAC in
B. subtilis [141] and is probably also present in Clostridium spp. [129]. The B. subtilis sigF gene product
(cF ) is essential for gene expression in the early
spore. It is not transcribed until shortly after the
start of sporulation [142] and its protein product is
speci¢cally activated within the developing forespore
after septation [143]. The spoIIAC gene, together
with spoIIAA and spoIIAB genes is located in the
spoA operon, which is controlled by cH [134]. The
cF activity depends on the phosphorylation state of
SpoIIAA, which is determined by the ATP/ADP ratio in the cell [82]. Phosphorylated SpoIIAA binds to
139
SpoIIAB, preventing SpoIIAB to bind to cF and
consequently inhibit transcription of cF -dependent
promoters [82]. The cF -factor is required for the appearance of two later acting sporulation-speci¢c cfactors, cE and cG , as well as for morphological
development of the forespore itself.
Based on the six known cF -dependent promoters
and analysis of several cF promoter point mutations a consensus sequence [129,144] containing
a 335 region, WGCATA, and a 310 region,
GGnRAYAMTW, separated by a spacer of 14 or
15 bp (Table 2) was derived.
3.4.3. Sigma E
Sigma-factor E is encoded by sigE (spoIIGB)
present in B. subtilis [145] and Clostridium acetobutylicum [129]. Sigma E is involved in the transcription of early sporulation genes in the mother-cell
compartment in B. subtilis. Transcription of sigE requires cA and phosphorylated SpoOA [146,147]. The
primary translation product of sigE, pro-cE , is inactive as a c-factor and appears just after the onset of
sporulation [148]. After formation of the septum
pro-cE is converted into active cE by removal of
29 N-terminal amino acids by a sporulation-speci¢c
protease SpoIIGA which is coexpressed with pro-cE
[148,149]. Processing of pro-cE only occurs after a
speci¢c signal protein SpoIIR, controlled by cF triggers the reaction [150]. Sigma E blocks formation of
a second polar septum in the mother cell by activating the spoIID [151] and spoIIID [152] genes and a
number of other genes [153]. These genes have in
common a promoter consensus sequence consisting
of a 335 region, GKCATATT and a 310 region,
CATACAMT, separated by a spacer of 13 to 15 bp
[154,155] (Table 2).
Results from amino acid substitution experiments
showed that nucleotide C in the 335 region is recognized by a histidine residue at position 219 of cE
[154]. A substitution of the glutamine residue at position 217 in cE of B. subtilis to arginine resulted in a
c-factor that could direct transcription from cK -dependent promoters [154], but no longer from cE -dependent promoters.
3.4.4. Sigma G
Sigma G is encoded by sigG (spoIIIG) and is like
cE present in B. subtilis [156] and in C. acetobutyli-
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cum [157]. SigG causes RNAP to transcribe the late
sporulation genes in the forespore. The B. subtilis cG
transcription is regulated by cF as well as being autoregulated [144,156,158]. Transcription of cG is induced shortly after septation. Like cF , cG activity is
inhibited by SpoAB and is presumably counteracted
by SpoIIAA [82] The cG -dependent genes encode a
family of small, acid-soluble spore proteins [158]
which are activated after the forespore is pinched
o¡ as a free protoplast within the mother cell. Sigma
G recognizes the consensus promoter elements 335,
TGAATA, and 310, CATACTA, separated by a
spacer of 17 or 18 bp [159] (Table 2).
3.4.5. Sigma K
Sigma-factor K is involved in the transcription of
late sporulation genes in the mother-cell compartment in Bacillus spp. and probably Clostridium spp.
as well [79,129]. In B. subtilis, cK transcription depends on a sporulation-site-speci¢c rearrangement of
the chromosome which joins the spoIVCB and
spoIIIC genes to a single cistron sigK [160]. The rearrangement is due to the site-speci¢c recombinase
SpoIVCA. Transcription of the spoIVCA gene is activated by SpoIIID [161]. The rearrangement does
not occur in Bacillus thuringiensis, Bacillus megaterium and C. acetobutylicum in which sigK is a contiguous gene [129,157]. Transcription of cK occurs
by cE RNAP and SpoIIID [162]. The product of
sigK in B. subtilis and B. thuringiensis is an inactive
pro-protein called pro-cK which is converted to active cK after proteolytic removal of 20 amino acids
[163]. Active cK is produced in the mother-cell compartment late in sporulation where it regulates the
formation of spore coat genes [164], promotes the
synthesis of dipicolinic acid synthetase [165] and initiates a negative feedback loop controlling the transcription of sigE [166].
Alignment of six cK -dependent promoters revealed
a 335 consensus promoter element of only two nucleotides, AC, and a 310 region, CATAnAnTA, separated by 16 or 17 nucleotides [167] (Table 2).
4. The c54-family
The c54 -family is structurally and functionally distinct from the c70 -family. These proteins have no
detectable sequence similarity with the primary cfactors. Based on the homology between c54 -proteins, three distinct regions have been recognized
(Fig. 2) [16]. Region I is glutamine rich and comprises 25 to 50 amino acids. This region is followed
by a more variable region II, which usually contains
between 60 and 110 amino acids with a signi¢cant
excess of acidic residues. The carboxyterminal region
III is some 400 amino acids long and contains the Xlink region [168], which has been shown to cross-link
to DNA and two well-conserved motifs: a potential
helix-turn-helix (HTH) region and the RpoN box.
Both motifs are involved in recognition of the promoter region of c54 -dependent promoters [169]. The
RpoN box is characterized by a stretch of ten conserved amino acids, ARRTVAKYRE. As assayed by
band shift analysis, single point mutations near amino acids 363 and 383 of E. coli RpoN destroyed the
ability of c54 to bind DNA [15].
The initiation of transcription of RNAP holoenzyme containing c54 di¡ers from that of the c70 -family [19]. Whereas the RNAP holoenzyme containing
a member of the c70 -family often initiates transcription in the absence of transcriptional activators,
transcription from all known c54 -dependent promoters requires the presence of an activator protein.
By contrast, the c54 holoenzyme can form a closed
promoter complex but is incapable of proceeding to
open complex formation in the absence of an activator protein [170]. The activator protein binds to an
enhancer which is located 100 bp or more upstream
of the transcriptional start site of a c54 promoter and
possesses a nucleoside triphosphatase activity by
which it catalyzes the open complex formation by
interaction with RNAP holoenzyme. The activator/
polymerase interaction often requires bending of the
DNA. Promoters without an intrinsic single bend in
the DNA between enhancer and promoter are dependent on the integration factor (IHF) which can
introduce a bend in a stretch of DNA [171]. The
open complex can be maintained without the presence of an activator. Several of the RpoN activators
have been characterized in di¡erent bacterial species
[172,173]. Examples are NtrC in Rhodobacter spp.,
Klebsiella pneumoniae and NifA in Rhizobium spp.
both involved in nitrogen ¢xation, DctD, involved
in dicarboxylate transport in Rhizobium spp., FhlA
activator of the formate regulon in E. coli [174] and
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XylR involved in the degradation of aromatic compounds in Pseudomonas putida [175].
Sigma 54 encoded by rpoN was ¢rst identi¢ed in
E. coli and S. typhimurium as the c-factor required
for transcription of nitrogen-regulated genes e.g. glutamine synthetase [176,177]. Today, a wide variety of
c54 -dependent genes of Gram-negative and Grampositive bacteria is known. These genes have in common that they are not essential for growth [19]. One
exception has to be made for some genes in M. xanthus because the rpoN product in this bacterium is
probably essential [178]. Examples of RpoN-dependent genes include those coding for proteins involved
in the formate dehydrogenase in E. coli, dicarboxylate transport in P. putida, Aztobacter vinelandii and
Rhizobium meliloti, ¢mbriae synthesis in P. aeruginosa, Moraxella bovis and Neisseria gonorrhoea, £agellar synthesis in C. crescentus and P. aeruginosa, levanase production in B. subtilis [173], nitrogen
¢xation in K. pneumoniae, Rhizobium sp. and Rhodobacter sp. and xylene degradation in P. putida. Most
c54 containing eubacterial species contain one single
c54 gene, but B. japonicum, and Rhodobacter sphaeroides contain two di¡erent rpoN genes [179,180]. Inactivation of one of these genes in B. japonicum and
R. sphaeroides has no in£uence on the phenotype of
these bacteria. Expression of rpoN is usually constitutive but in some cases, such as in Rhodobacter capsulatus, it is regulated by oxygen and nitrogen levels
[181]. In C. crescentus it is regulated temporally during the cell cycle [182]. In B. japonicum rpoN1 is
regulated in response to oxygen while rpoN2 is negatively autoregulated [180]. Negatively autoregulated
rpoN genes are also found in P. putida and Rhizobium etli [183].
Together with at least one activator, c54 enables
RNAP to transcribe c54 -dependent promoter sequences (TGGCAC-N5-TTGC) located between positions 326 and 311 ( þ 1) of the transcription start
site [19] (Table 2). Changes of only 1 bp in the spacing between the GG and GC motifs inactivate the
promoter [19].
5. Factors that a¡ect transcription initiation
The sequence of promoter elements is just one of
many factors that determine the overall e¤ciency of
141
a particular promoter [184]. The binding of the
RNAP holoenzyme to the promoter and the transition from closed to open complex are a¡ected by the
DNA conformation in the promoter region and by
accessory proteins.
Gene expression depends on the supercoiling of
the genome, which is normally negative [185]. Local
di¡erences in the level of supercoiling exist and can
be modulated by environmental signals such as temperature, anaerobiosis and osmolarity. The density
of DNA supercoils a¡ects the £exibility of the promoter spacer region in both closed and open complex formation and thus a¡ects initiation of transcription by the RNAP holoenzyme in a positive or
negative way [186].
Many sequence-speci¢c DNA-binding proteins are
known that can in£uence promoter activity. For example there are 40 proteins which can activate or
prevent transcription of c70 -regulated promoters in
E. coli [187]. These proteins allow the bacterium to
regulate the expression of subsets of genes in response to external and internal stimuli. Genes that
are responding to a common stimulus often use the
same regulatory elements and are therefore referred
to as being part of a regulon. Activators of these
promoters usually bind to the DNA between positions 330 and 380 of the transcription start site
[187]. The 335 sequences of these promoters often
show a poor homology to the standard c70 335 promoter sequence [188]. Repressors bind primarily to
locations that overlap with the polymerase-binding
site [187]. Promoters recognized by the c54 holoenzyme are, however, always subject to positive control. Activators of c54 -dependent promoters typically
bind around 100 bp upstream of the promoter, but
in some cases this is more than 1 kb [19].
Histone-like proteins, such as H-NS in E. coli,
may inhibit transcription initiation. H-NS binds anywhere on DNA, but it shows a preference for curved
DNA [189]. The transcription of many stationaryphase-responsive genes is inhibited by H-NS [41].
Other, non-proteinaceous factors, that can also
a¡ect promoter activity are DNA methylation and
the regulatory nucleotide ppGpp. DNA methylation
may a¡ect the binding of RNAP holoenzyme or
transcriptional regulators. Several ¢mbrial operons
in E. coli are regulated by this mechanism [190].
ppGpp is synthesized by RelA, an enzyme that is
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activated in response to amino acid starvation in the
so-called stringent response [191]. High concentrations of ppGpp result in the cessation of RNA synthesis and the down regulation of energy-consuming
processes. Some promoters are activated by ppGpp,
like the RpoS promoter of the general stress c-factor
S [192]. Promoters which are negatively regulated by
ppGpp all contain a G+C rich nucleotide element
between the 310 promoter element and the transcriptional start site [191,193]. This element is called
the `stringent box' or `discriminator'. In E. coli, it
has the consensus sequence GCGCCnCC [193].
6. Anti-sigma-factors
Proteins that negatively regulate transcription by
interaction with a speci¢c c-factor are known as
anti-c-factors [82]. The binding of an anti-c-factor
to its cognate c-factor is probably reversible. It enables the cell to respond adequately to environmental signals when the alternative c-factor is already
available and does not need to be synthesized. The
anti-c-factor binds the c-factor until it is needed for
transcription. In S. typhimurium, the activity of c28 is
regulated by FlgM [194]. FlgM functions as an antisigma-factor and regulates its own expression. It
binds to c28 and blocks its activity until the hookbasal body is assembled into the membrane, at which
time expression of £agellin and other £agellar genes
is derepressed. After completion of the basal-body
hook formation, FlgM is exported through the
basal-body hook liberating c28 . Once the £agellum
¢lament has been capped, FlgM can no longer be
exported. FlgM then binds c28 and the synthesis of
the £agellin and expression of chemotaxis genes
ceases.
Anti-sigma-factors of sporulation, stress and ECF
related c-factors are also known. In B. subtilis three
c-factors are negatively regulated by an anti-c-factor. The spore formation is mediated by the anti-cfactor SpoIIAB which interacts with the early sporulation cF and the late sporulation cG [195,196].
Anti-c-factor RsbW is bound to the stress related
cB in exponentially growing cells [82]. The regulation
of SpoIIAB and RsbW is similar. In conditions of
ATP excess these anti-c-factors are bound to their
cognate c-factor. In conditions of ADP excess
SpoIIAB and RsbW are bound to the dephosphorylated anti-anti-c-factor SpoIIAA and RsbV respectively, releasing the active c-factor. The ECF c-factor CarQ is negatively regulated by anti-c-factor
CarR [103]. In the dark CarR is bound to CarQ.
Light inactivates CarR by degradation or light-inhibition translation of CarR [103]. AlgU, an ECF cfactor of P. aeruginosa, regulates the alginate biosynthesis and is negatively regulated by anti-c-factor
MucA [197]. The cE of E. coli is negatively regulated
by RseB and anti-c-factor RseA [198,199]. RseA is
an inner membrane protein of which the cytoplasmic
domain binds to cE and inhibits cE directed transcription. RseB is a periplasmic protein and speci¢cally interacts with the C-terminal periplasmic domain of RseA.
7. Conclusions
Bacterial genome projects are proving important
information about the presence of genes for various
c-factors in di¡erent species. When a c-factor is
identi¢ed in a bacterial genome, it is reasonable to
assume that genes regulated by this c-factor in other
bacteria are similarly regulated in this organism. For
example when a c28 homolog is identi¢ed, it is highly
probable that some of the £agellar genes of this bacterium are regulated by c28 . The genome of Haemophilus in£uenzae codes for four c-factors: c70 , the
heat shock related c32 and two c-factors belonging
to the ECF family [200]. Synechocystis contains eight
di¡erent c-factors: one primary c-factor RpoD1,
four c-factors belonging to the nonessential primary-like c-factors, two c-factors belonging to the
ECF family and the sporulation related c-factor cF
[201]. The small genomes of Helicobacter pylori and
Borrelia burgdorferi contain only three c-factors
[202,203]. H. pylori contains c70 , the £agella related
c28 and c54 . Instead of c28 B. burgdorferi harbors the
stationary-phase c-factor c38 . The seven c-factors of
E. coli are c70 , c38 , c 32 , c28 , c54 and the ECF cfactors cE and cFecI [204]. Analysis of the genome of
B. subtilis revealed four new potential ECF c-factors
making it a total of 14 di¡erent c-factors: primary
c-factor cA , heat shock c-factor cB , £agella related
cD , ¢ve sporulation related c-factors, ¢ve ECF cfactors and cL belonging to the c54 -family [100].
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To date, B. subtilis is the species with the largest
number of c-factors, even though it does not contain
the largest genome size of the bacteria described.
There is however, a relationship between the number
of c-factors, the bacterial genome size and the more
severe conditions a bacteria can survive.
Consensus sequences derived from experimentally
determined promoter sequences are valuable for the
identi¢cation of promoter sequences in genomic
DNA sequences. The number of genes from which
a hypothetical protein can be translated is increasing
rapidly. Identi¢cation of promoters in front of these
genes by the use of promoter consensus sequences
can help to classify these genes and may even help
to predict a possible function for the encoded proteins.
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