Chapter One - Physiological Role of Two-Component Signal Transduction Systems in Food-Associated Lactic Acid Bacteria
Introduction
Regulation of cell physiology in response to changing conditions is a must for survival in the competitive environments that bacteria often face. Signal transduction systems are key players in the regulatory circuits that modulate bacterial physiology. Among them, two-component systems (TCSs) have been subjected to intensive research since their discovery (Nixon, Ronson, & Ausubel, 1986). TCSs are signal transduction pathways typically consisting of a sensor histidine kinase (HK), usually membrane bound, and a cytoplasmic response regulator (RR). Both proteins present a modular structure (Fig. 1). The HK has an N-terminal sensory domain that monitors the environmental signals and two modules involved in the phosphorylation reaction. The first domain holds the phosphorylatable His (histidine-phosphotransfer domain, Dhp). The second domain (CA domain) holds the ATP binding site and catalyzes the phosphorylation of the Dhp domain. The RR presents a conserved receiver domain (REC), where the phosphorylatable Asp residue is located, and a C-terminal effector domain. The domains involved in the phosphorylation reaction are homologous in all TCSs while the sensory and output domains of the HK and RR, respectively, are characteristic for each TCS and determine its specificity.
In general, detection of a specific stimulus triggers the HK autophosphorylation in the conserved His residue at the DHp domain and the subsequent transference of the phosphate group to the conserved Asp residue at the REC domain of its cognate RR (Fig. 1). Phosphorylation of the RR modulates its activity, which usually involves transcriptional regulation mediated by its C-terminal effector domain (Stock, Robinson, & Goudreau, 2000). HKs often also act as phosphatases for their cognate response regulators (Huynh & Stewart, 2011); in other cases, dephosphorylation of RRs is carried out by auxiliary phosphatases (Silversmith, 2010) or spontaneous hydrolysis. The final output response results from the balance of kinase and phosphatase activities. The mechanisms of signal transfer and regulation operated by TCSs will not be covered here as they have been extensively reviewed elsewhere (Casino et al., 2010, Galperin, 2010, Gao and Stock, 2009, Groisman, 2016, Huynh and Stewart, 2011, Jung et al., 2012, Krell et al., 2010, Mascher et al., 2006, Podgornaia and Laub, 2013, Salazar and Laub, 2015, Stock et al., 2000, Zschiedrich et al., 2016). These studies have shown that in many cases TCSs are integrated in complex regulatory networks that often involve a number of TCSs as well as other sensors.
The analyses of the HK and RR coding sequences and genetic organization have shown that TCS proteins belong to a limited number of families, which share common ancestry and domain structure (Whitworth & Cock, 2009). This has led to the proposal of a number of classification schemes based on phylogenetic reconstructions of conserved domains (Fabret et al., 1999, Grebe and Stock, 1999) or on the domain composition of TCS proteins (Galperin, 2006). Furthermore, TCSs are usually encoded by adjacent genes (although orphan genes, that is, unpaired HK or RR encoding genes, can also be found) and are arranged in the same order and orientation (Koretke, Lupas, Warren, Rosenberg, & Brown, 2000). The evolution of TCS has been the subject of a number of studies that have evidenced that coevolution of HK and RR pairs has been prevalent although examples of recruitment, i.e., duplication of one component and association with a nonorthologous partner, could also be observed (Alm et al., 2006, Koretke et al., 2000).
Beyond the basic scheme of signal transfer outlined earlier, more complex phosphotransfer relays also exist, which involve multiple phosphotransfer reactions among domains that can be found on separate polypeptides or as part of multidomain proteins (Appleby et al., 1996, Zhang, 2005). Besides, other auxiliary proteins can modulate the activities of TCSs (Buelow and Raivio, 2010, Gao and Stock, 2009). Furthermore, TCS can also integrate other signals through additional cytoplasmic sensory domains or through metabolites that can affect the phosphorylation state of the TCS proteins (Gao and Stock, 2009, Krell et al., 2010, Szurmant et al., 2007). Among the cytoplasmic sensory domains identified in HKs, PAS (PER, ARNT, SIM) and GAF (c-GMP–specific and c-GMP–stimulated phosphodiesterases, Anabaena adenylate cyclases and Escherichia coli FhlA) are the most common (Galperin et al., 2001, Szurmant et al., 2007). PAS domains can receive signals by several mechanisms including signal binding to the PAS domain cavity, signal perception by cofactor-containing PAS domains, signal binding at the PAS domain–membrane interface, and signal-mediated modulation of inter-PAS domain disulfide bonds (reviewed in Krell et al., 2010). The role of GAF domains in TCS remains undetermined in many cases. It has been shown that GAF domains bind heme in some redox or oxygen-sensing HKs (Kumar, Toledo, Patel, Lancaster, & Steyn, 2007) and cyanobacterial photoreceptor HKs involved in phototaxis covalently bind tetrapyrrole pigments through their GAF domains (Ikeuchi & Ishizuka, 2008). A recent study has shown that the GAF domain of the Synechocystis sp. PCC 6803 cytoplasmic HK Hik2 possibly functions as a chloride sensor (Kotajima, Shiraiwa, & Suzuki, 2014). Some metabolites may also affect the phosphorylation state of TCSs. Several RRs have been shown to be phosphorylated by acetyl phosphate (acetyl-P) thus providing a possible link between TCS activity and metabolic state (Wolfe, 2010). Although some studies have noted that HK phosphatase activity may prevent this HK-independent phosphorylation, recent studies support the view of acetyl-P-dependent RR phosphorylation as a mechanism of regulation of TCS activity (Lima et al., 2012, Schrecke et al., 2013). Polyphosphate can also act as a phosphoryl donor for the MprB sensor protein of Mycobacterium tuberculosis (Sureka et al., 2007). Finally, other signal transducing pathways, such as those operated by Ser/Thr kinases, can modulate the activity of TCSs via posttranslational modification (Burnside & Rajagopal, 2012).
TCSs participate in most aspects of bacterial physiology, including motility, sporulation, competence, nutrient uptake, stress response, central metabolism, and virulence. TCSs are found in varying numbers in bacteria although, generally, bacteria with larger genomes encode more TCSs (Galperin, 2005, Sheng et al., 2012, Ulrich et al., 2005, Wuichet et al., 2010). In addition, the number of TCSs correlates with ecological niches. Free-living bacteria that inhabit changing or diverse environments usually harbor more TCSs than bacteria that live in constant environments, such as pathogenic bacteria, suggesting a correlation between metabolic versatility and number of TCSs (Capra and Laub, 2012, Galperin, 2005). In contrast to bacteria, TCSs are far less common in eukaryotes and completely absent in mammals. This, together with the role of some TCSs in pathogenesis, has driven their interest as potential targets for antimicrobial drugs. This situation also reflects on lactic acid bacteria (LAB) where a number of TCSs of pathogenic streptococci have been thoroughly characterized, whereas far less information is available about TCSs of commensal LAB.
The term lactic acid bacteria comprises a broad group of microorganisms characterized by their ability to degrade sugars mainly into lactic acid (Orla-Jensen, 1919). Originally classified on the basis of phenotypic traits that led to protracted controversies, the use of phylogenetic techniques based on DNA sequencing has shown that the major group of genera of LAB diverged from a common ancestor (Schleifer & Ludwig, 1995). It is becoming increasingly accepted by the scientific community that LAB species constitute the order Lactobacillales (phylum Firmicutes) and other species that have been traditionally considered as LAB must not be included in this group (Vandamme, De Bruyne, & Pot, 2014). The order Lactobacillales currently consists of six families: Aerococcaceae, Carnobacteriaceae, Enterococcaceae, Lactobacillaceae, Leuconostocaceae, and Streptococcaceae. However, even this family classification is questionable. Phylogenomic analyses have shown that, within the genus Lactobacillus, other genera belonging to families Lactobacillaceae and Leuconostocaceae, such as Fructobacillus, Leuconostoc, Oenococcus, Pediococcus and Weissella, are grouped within the lactobacilli as subclades (Claesson and van Sinderen, 2008, Makarova et al., 2006, Sun et al., 2015, Zhang et al., 2011). For the purposes of this review, we will therefore consider the members of families Lactobacillaceae and Leuconostocaceae as a single phylogenetic unit, and we will refer to them as lactobacilli throughout the text.
LAB have long been used for the transformation of raw foodstuffs into a variety of fermented products as their growth is associated with the acidification and production of antimicrobial substances that prevent the proliferation of pathogenic or spoilage organisms. Furthermore, the enzymatic processes associated to their growth contribute to the characteristic flavor and texture of these products. The continued use of LAB in these processes led to the adaptation of some strains (domestication) to specific food systems through repeated inoculation and selection. This process implied major genomic changes in food LAB strains, mainly loss of gene functions as a consequence of the adaptation to a nutrient-rich environment, but also gene gains associated to relevant technological properties (Douglas and Klaenhammer, 2010, Makarova et al., 2006). Other LAB, naturally associated to mucosal surfaces of humans and animals, are also used as probiotics since they are attributed health benefits (Tannock, 2004). Lactobacilli, in contrast to streptococci, have been rarely associated to disease (Cannon et al., 2005, Kamboj et al., 2015), but there is increasing concern about their possible role as reservoirs of potentially transmissible antimicrobial resistance genes (Devirgiliis et al., 2013, Jaimee and Halami, 2016). This highlights the need to understand not only the antibiotic resistance mechanisms of pathogenic bacteria, but also those present in commensal bacteria that are usually recognized as GRAS/QPS organisms such as most lactobacilli.
Due to its involvement in food production and health, leuconostoc, and specially lactobacilli, have been the subject of intensive research. Despite this, the role of TCSs in their physiology has been somehow neglected and our current knowledge on these systems is rather limited compared to other LAB such as streptococci. The aim of this review is to summarize the available evidence on the physiological role of TCSs in Lactobacillaceae and Leuconostocaceae as they comprise most food-associated LAB as well as many commensal species associated to plants and animals.
Section snippets
Number, Distribution, and Classification of TCSs in Lactobacilli
To our knowledge, only one study has dealt with the number and classification of TCSs in lactobacilli in an evolutionary setting using 19 genomic sequences of lactobacilli available at the time (Zúñiga, Gómez-Escoín, & González-Candelas, 2011). In this review, we have updated this previous work and used 98 complete genome sequences available at the Microbial Genome Database for Comparative Analysis (MBGD; http://mbgd.genome.ad.jp) (Uchiyama, Mihara, Nishide, & Chiba, 2015). The number of
Physiological Roles of TCSs in Lactobacilli
TCSs regulate essential physiological processes in many bacteria, and evidence obtained so far indicates that this is also the case in lactobacilli. The first indication on a functional role of TCSs of lactobacilli came from studies of bacteriocin production by lactobacilli. The genetic analyses of bacteriocin gene clusters revealed the presence of TCS-encoding genes in these clusters (Axelsson and Holck, 1995, Diep et al., 1994, Hühne et al., 1996). In Lactobacillus sakei, it was shown that
Concluding Remarks
Physiology and genetics of lactobacilli have been an important research area in the past decades due to their relevance in food production and health. However, the study of signal transduction pathways in these organisms has received relatively little attention. The progress made in the study of TCSs in lactobacilli has evidenced that these systems play important roles in the cell physiology of lactobacilli. The role of TCSs in bacteriocin production is relatively well known nowadays, but the
References (210)
- et al.
Signal transduction via the multi-step phosphorelay: Not necessarily a road less traveled
Cell
(1996) - et al.
Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator
Structure
(2002) - et al.
Regulation of prokaryotic gene expression by eukaryotic-like enzymes
Current Opinion in Microbiology
(2012) - et al.
The mechanism of signal transduction by two-component systems
Current Opinion in Structural Biology
(2010) - et al.
A two component system is involved in acid adaptation of Lactobacillus delbrueckii subsp. bulgaricus
Microbiological Research
(2012) - et al.
Molecular adaptation of sourdough Lactobacillus plantarum DC400 under co-cultivation with other lactobacilli
Research in Microbiology
(2009) - et al.
An overview of the mosaic bacteriocin pln loci from Lactobacillus plantarum
Peptides
(2009) Diversity of structure and function of response regulator output domains
Current Opinion in Microbiology
(2010)- et al.
Novel domains of the prokaryotic two-component signal transduction systems
FEMS Microbiology Letters
(2001) - et al.
The histidine protein kinase superfamily
Advances in Microbial Physiology
(1999)
The Lactococcus lactis CodY regulon: Identification of a conserved cis-regulatory element
Journal of Biological Chemistry
C4-dicarboxylate carriers and sensors in bacteria
Biochimica et Biophysica Acta (BBA) – Bioenergetics
Histidine kinases and response regulators in networks
Current Opinion in Microbiology
The fumarate/succinate antiporter DcuB of Escherichia coli is a bifunctional protein with sites for regulation of DcuS-dependent gene expression
Journal of Biological Chemistry
Autoregulation of nisin biosynthesis in Lactococcus lactis by signal transduction
Journal of Biological Chemistry
Peptide and amino acid metabolism is controlled by an OmpR-family response regulator in Lactobacillus casei
Molecular Microbiology
Influence of two-component signal transduction systems of Lactobacillus casei BL23 on tolerance to stress conditions
Applied and Environmental Microbiology
The evolution of two-component systems in bacteria reveals different strategies for niche adaptation
PLoS Computational Biology
Antagonistic activity of Lactobacillus plantarum C11: Two new Two-peptide bacteriocins, plantaricins EF and JK, and the induction factor plantaricin A
Applied and Environmental Microbiology
Regulation of the transport system for C4-dicarboxylic acids in Bacillus subtilis
Microbiology
The genes involved in production of and immunity to sakacin A, a bacteriocin from Lactobacillus sake Lb706
Journal of Bacteriology
Cloning and nucleotide sequence of a gene from Lactobacillus sake Lb706 necessary for sakacin A production and immunity
Applied and Environmental Microbiology
Microarray analysis of a two-component regulatory system involved in acid resistance and proteolytic activity in Lactobacillus acidophilus
Applied and Environmental Microbiology
Identification and purification of a protein that induces production of the Lactobacillus acidophilus bacteriocin lactacin B
Applied and Environmental Microbiology
The essential YycFG two-component system controls cell wall metabolism in Bacillus subtilis
Molecular Microbiology
Involvement of sensor kinases in the stress tolerance response of Streptococcus mutans
Journal of Bacteriology
Multidrug resistance in Lactococcus lactis: Evidence for ATP-dependent drug extrusion from the inner leaflet of the cytoplasmic membrane
EMBO Journal
Regulation of anaerobic citrate metabolism in Klebsiella pneumoniae
Molecular Microbiology
Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria?
Nature Reviews Microbiology
Three (and more) component regulatory systems – auxiliary regulators of bacterial histidine kinases
Molecular Microbiology
Pathogenic relevance of Lactobacillus: A retrospective review of over 200 cases
European Journal of Clinical Microbiology and Infectious Diseases
The evolution of two-component signal transduction systems
Annual Review of Microbiology
Co-culture-inducible bacteriocin production in lactic acid bacteria
Applied Microbiology and Biotechnology
Isolation and characterization of pediocin L50, a new bacteriocin from Pediococcus acidilactici with a broad inhibitory spectrum
Applied and Environmental Microbiology
Lactobacillus phylogenomics – towards a reclassification of the genus
International Journal of Systematic and Evolutionary Microbiology
The ABC transporter AnrAB contributes to the innate resistance of Listeria monocytogenes to nisin, bacitracin, and various beta-lactam antibiotics
Antimicrobial Agents and Chemotherapy
Chemiosmotic energy from malolactic fermentation
Journal of Bacteriology
Update on antibiotic resistance in foodborne Lactobacillus and Lactococcus species
Frontiers in Microbiology
The synthesis of the bacteriocin sakacin A is a temperature-sensitive process regulated by a pheromone peptide through a three-component regulatory system
Microbiology
A bacteriocin-like peptide induces bacteriocin synthesis in Lactobacillus plantarum C11
Molecular Microbiology
Characterization of the locus responsible for the bacteriocin production in Lactobacillus plantarum C11
Journal of Bacteriology
The gene encoding plantaricin A, a bacteriocin from Lactobacillus plantarum C11, is located on the same transcription unit as an agr-like regulatory system
Applied and Environmental Microbiology
Evidence for dual functionality of the operon plnABCD in the regulation of bacteriocin production in Lactobacillus plantarum
Molecular Microbiology
Inducible bacteriocin production in Lactobacillus is regulated by differential expression of the pln operons and by two antagonizing response regulators, the activity of which is enhanced upon phosphorylation
Molecular Microbiology
Coevolution of ABC transporters and two-component regulatory systems as resistance modules against antimicrobial peptides in Firmicutes bacteria
Journal of Bacteriology
Identification of an operon and inducing peptide involved in the production of lactacin B by Lactobacillus acidophilus
Journal of Applied Microbiology
Genomic evolution of domesticated microorganisms
Annual Review of Food Science and Technology
Comparative genomic and functional analysis of 100 Lactobacillus rhamnosus strains and their comparison with strain GG
PLoS Genetics
Lantibiotic resistance
Microbiology and Molecular Biology Reviews
New insights into the WalK/WalR (YycG/YycF) essential signal transduction pathway reveal a major role in controlling cell wall metabolism and biofilm formation in Staphylococcus aureus
Journal of Bacteriology
Cited by (31)
Comparative genomics reveals the organic acid biosynthesis metabolic pathways among five lactic acid bacterial species isolated from fermented vegetables
2022, New BiotechnologyCitation Excerpt :L. plantarum PC1–1, L. buchneri PC-C1, and P. pentosaceus PC2–1(F2) contained two co-transcribed operons encoding the signal transduction histidine kinase that regulates the metabolism of citrate/malate and the LytR family transcriptional regulatory protein. Previous studies have considered two-component systems as universal signal transduction pathways mainly associated with organic acid biosynthesis, production of bacteriocins, and other physiological processes, such as resistance to antimicrobial peptides, control of nitrogen metabolism, and response to stress [77]. Transcription is part of the critical processes of gene expression for secondary metabolism in LAB, regulation of which promotes their ability to adapt to varying environmental settings [78,79].
Proteomics reveal the protective effects of chlorogenic acid on Enterococcus faecium Q233 in a simulated pro-oxidant colonic environment
2022, Food Research InternationalCitation Excerpt :The two-component systems are bacterial mechanisms of adaptation to environmental changes. They are composed by a sensor histidine kinase that autophosphorylate and subsequently transfer the phosphate group to their cognate response regulators thus modulating their activity, usually as transcriptional regulators (Monedero et al., 2017). In line with the present results, Zhou et al. (2010) found an upregulation of one gene encoding for histidine kinases in Desulfovibrio vulgaris Hildenborough incubated with H2O2.
Pangenome analyses of LuxS-coding genes and enzymatic repertoires in cocoa-related lactic acid bacteria
2021, GenomicsCitation Excerpt :LAB members present a ubiquitous distribution, with lifestyles varying from nomadic or free-living, to vertebrate- or invertebrate-adapted [2]. LAB also present high genomic variability, being usually characterized by inhabiting nutrient-rich environments, with trend to reduction of genome size, especially in food-derived strains [3,4]. Thus, it is not uncommon to observe a highly diversified repertoire for metabolism of carbohydrates among strains of the same LAB species, owing to strain-specific adaptations [3].
Mechanism of nutrient removal enhancement in low carbon/nitrogen wastewater by a novel high-frequency micro-aeration/anoxic (HMOA) mode
2021, ChemosphereCitation Excerpt :The results demonstrated that pathways involved in the two-component system were most highly expressed in HMOA. The two-component system is the signal transduction system in microorganisms, and it plays a major role in adaptation to changing environmental conditions in activated sludge process (Zschiedrich et al., 2016; Monedero et al., 2017). The up-regulation of these pathways indicated that the HMOA mode promoted the survival of microorganisms cultivated under low C/N conditions by increasing microbial transduction of environmental information (i.e., DO and ammonia).