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Carbohydrate Utilization in Bacteria: Making the Most Out of Sugars with the Help of Small Regulatory RNAs

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  • Authors: Svetlana Durica-Mitic*1, Yvonne Göpel*2, Boris Görke3
  • Editors: Gisela Storz4, Kai Papenfort5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria; 2: Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria; 3: Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria; 4: Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; 5: Department of Biology I, Microbiology, LMU Munich, Martinsried, Germany
    • Source: microbiolspec March 2018 vol. 6 no. 2 doi:10.1128/microbiolspec.RWR-0013-2017
  • Received 27 November 2017 Accepted 03 January 2018 Published 23 March 2018
  • Boris Görke, [email protected]
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  • Abstract:

    Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate metabolism is governed by complex regulatory networks including posttranscriptional mechanisms that involve small regulatory RNAs (sRNAs) and RNA-binding proteins. sRNAs limit the response to substrate availability and set the threshold or time required for induction and repression of carbohydrate utilization systems. Carbon catabolite repression (CCR) also involves sRNAs. In , sRNA Spot 42 cooperates with the transcriptional regulator cyclic AMP (cAMP)-receptor protein (CRP) to repress secondary carbohydrate utilization genes when a preferred sugar is consumed. In pseudomonads, CCR operates entirely at the posttranscriptional level, involving RNA-binding protein Hfq and decoy sRNA CrcZ. Moreover, sRNAs coordinate fluxes through central carbohydrate metabolic pathways with carbohydrate availability. In Gram-negative bacteria, the interplay between RNA-binding protein CsrA and its cognate sRNAs regulates glycolysis and gluconeogenesis in response to signals derived from metabolism. Spot 42 and cAMP-CRP jointly downregulate tricarboxylic acid cycle activity when glycolytic carbon sources are ample. In addition, bacteria use sRNAs to reprogram carbohydrate metabolism in response to anaerobiosis and iron limitation. Finally, sRNAs also provide homeostasis of essential anabolic pathways, as exemplified by the hexosamine pathway providing cell envelope precursors. In this review, we discuss the manifold roles of bacterial sRNAs in regulation of carbon source uptake and utilization, substrate prioritization, and metabolism.

  • Citation: Durica-Mitic* S, Göpel* Y, Görke B. 2018. Carbohydrate Utilization in Bacteria: Making the Most Out of Sugars with the Help of Small Regulatory RNAs. Microbiol Spectrum 6(2):RWR-0013-2017. doi:10.1128/microbiolspec.RWR-0013-2017.

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/content/journal/microbiolspec/10.1128/microbiolspec.RWR-0013-2017
2018-03-23
2020-04-09

Abstract:

Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate metabolism is governed by complex regulatory networks including posttranscriptional mechanisms that involve small regulatory RNAs (sRNAs) and RNA-binding proteins. sRNAs limit the response to substrate availability and set the threshold or time required for induction and repression of carbohydrate utilization systems. Carbon catabolite repression (CCR) also involves sRNAs. In , sRNA Spot 42 cooperates with the transcriptional regulator cyclic AMP (cAMP)-receptor protein (CRP) to repress secondary carbohydrate utilization genes when a preferred sugar is consumed. In pseudomonads, CCR operates entirely at the posttranscriptional level, involving RNA-binding protein Hfq and decoy sRNA CrcZ. Moreover, sRNAs coordinate fluxes through central carbohydrate metabolic pathways with carbohydrate availability. In Gram-negative bacteria, the interplay between RNA-binding protein CsrA and its cognate sRNAs regulates glycolysis and gluconeogenesis in response to signals derived from metabolism. Spot 42 and cAMP-CRP jointly downregulate tricarboxylic acid cycle activity when glycolytic carbon sources are ample. In addition, bacteria use sRNAs to reprogram carbohydrate metabolism in response to anaerobiosis and iron limitation. Finally, sRNAs also provide homeostasis of essential anabolic pathways, as exemplified by the hexosamine pathway providing cell envelope precursors. In this review, we discuss the manifold roles of bacterial sRNAs in regulation of carbon source uptake and utilization, substrate prioritization, and metabolism.

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Carbohydrate Utilization in Bacteria: Making the Most Out of Sugars with the Help of Small Regulatory RNAs
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Citation: Durica-Mitic* S, Göpel* Y, Görke B. 2018. Carbohydrate utilization in bacteria: making the most out of sugars with the help of small regulatory rnas. microbiolspec 6(2): doi:10.1128/microbiolspec.RWR-0013-2017
/content/microbiolspec/10.1128/microbiolspec.RWR-0013-2017.fig1
FIGURE 1
Manifold roles of sRNAs in regulation of carbohydrate metabolism in bacteria. The figure summarizes the major roles of sRNAs (depicted in red) in regulation of carbohydrate metabolism in bacteria. (A) Regulation of uptake and utilization of particular carbohydrates by sRNAs in various species. In , the -encoded sRNA SgrS counteracts phosphosugar stress through repression of glucose transporters and activation of the sugar phosphatase YigL. sRNA ChiX downregulates the chitosugar-specific porin ChiP, setting the threshold concentration for induction of degrading enzymes. Further examples include regulation of host glycan and mannitol uptake by -encoded sRNAs in and species, respectively. (B) Role of sRNAs in CCR. In and , the sRNA Spot 42 represses genes for utilization of secondary carbon sources. Spot 42 is repressed by cAMP-CRP and therefore only active in the presence of preferred sugars generating low cAMP levels. In , translation of mRNAs for utilization of secondary carbon sources is repressed by Hfq. In the absence of preferred substrates, the CbrA/CbrB TCS activates expression of the decoy sRNA CrcZ, titrating Hfq from target transcripts. (C) sRNAs coordinate carbohydrate metabolism with carbohydrate, oxygen, and iron availability. The RNA-binding protein CsrA activates glycolysis and represses gluconeogenesis by binding to corresponding RNAs. CsrA activity is counteracted through sequestration by sRNAs CsrB/CsrC, whose levels are regulated by signals from metabolism. In the absence of oxygen, sRNAs such as FnrS in and RoxS in redirect metabolism from oxidative phosphorylation to anaerobic respiration or fermentation. Upon iron starvation, sRNA RyhB represses TCA cycle enzymes to save iron for essential processes. (D) Example of an anabolic pathway regulated by sRNAs. In , two homologous sRNAs regulate the key enzyme GlmS to achieve homeostasis of glucosamine-6-phosphate (glucosamine-6-P), an essential precursor for cell envelope synthesis.
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FIGURE 1

Manifold roles of sRNAs in regulation of carbohydrate metabolism in bacteria. The figure summarizes the major roles of sRNAs (depicted in red) in regulation of carbohydrate metabolism in bacteria. (A) Regulation of uptake and utilization of particular carbohydrates by sRNAs in various species. In , the -encoded sRNA SgrS counteracts phosphosugar stress through repression of glucose transporters and activation of the sugar phosphatase YigL. sRNA ChiX downregulates the chitosugar-specific porin ChiP, setting the threshold concentration for induction of degrading enzymes. Further examples include regulation of host glycan and mannitol uptake by -encoded sRNAs in and species, respectively. (B) Role of sRNAs in CCR. In and , the sRNA Spot 42 represses genes for utilization of secondary carbon sources. Spot 42 is repressed by cAMP-CRP and therefore only active in the presence of preferred sugars generating low cAMP levels. In , translation of mRNAs for utilization of secondary carbon sources is repressed by Hfq. In the absence of preferred substrates, the CbrA/CbrB TCS activates expression of the decoy sRNA CrcZ, titrating Hfq from target transcripts. (C) sRNAs coordinate carbohydrate metabolism with carbohydrate, oxygen, and iron availability. The RNA-binding protein CsrA activates glycolysis and represses gluconeogenesis by binding to corresponding RNAs. CsrA activity is counteracted through sequestration by sRNAs CsrB/CsrC, whose levels are regulated by signals from metabolism. In the absence of oxygen, sRNAs such as FnrS in and RoxS in redirect metabolism from oxidative phosphorylation to anaerobic respiration or fermentation. Upon iron starvation, sRNA RyhB represses TCA cycle enzymes to save iron for essential processes. (D) Example of an anabolic pathway regulated by sRNAs. In , two homologous sRNAs regulate the key enzyme GlmS to achieve homeostasis of glucosamine-6-phosphate (glucosamine-6-P), an essential precursor for cell envelope synthesis.

Source: microbiolspec March 2018 vol. 6 no. 2 doi:10.1128/microbiolspec.RWR-0013-2017
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FIGURE 2
The transcriptional regulator cAMP-CRP and sRNA Spot 42 cooperate to trigger CCR in . (A) CRP and Spot 42 participate in coherent feedforward loops to prevent utilization of the indicated secondary carbon sources when the preferred carbon source glucose is present. In addition to cAMP-CRP, Spot 42 is regulated by base-pairing with the sponge RNA PspH. (B) The validated Spot 42 regulon to date. Target genes that are also positively controlled by cAMP-CRP at the level of transcription are boxed. Microarray analysis of Spot 42 pulse expression ( 75 ) and improved software prediction algorithms ( 32 , 76 ) fostered the identification of most targets. Additional targets were identified by human inference or by a CLIP-seq approach mapping Hfq binding sites on a global scale ( 74 , 82 , 173 , 181 ). Several of these targets were recovered by RIL-seq ( 77 ).
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FIGURE 2

The transcriptional regulator cAMP-CRP and sRNA Spot 42 cooperate to trigger CCR in . (A) CRP and Spot 42 participate in coherent feedforward loops to prevent utilization of the indicated secondary carbon sources when the preferred carbon source glucose is present. In addition to cAMP-CRP, Spot 42 is regulated by base-pairing with the sponge RNA PspH. (B) The validated Spot 42 regulon to date. Target genes that are also positively controlled by cAMP-CRP at the level of transcription are boxed. Microarray analysis of Spot 42 pulse expression ( 75 ) and improved software prediction algorithms ( 32 , 76 ) fostered the identification of most targets. Additional targets were identified by human inference or by a CLIP-seq approach mapping Hfq binding sites on a global scale ( 74 , 82 , 173 , 181 ). Several of these targets were recovered by RIL-seq ( 77 ).

Source: microbiolspec March 2018 vol. 6 no. 2 doi:10.1128/microbiolspec.RWR-0013-2017
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FIGURE 3
Posttranscriptional regulation of central carbon metabolic pathways in . Effects of sRNAs (depicted in red) and of the RNA-binding protein CsrA (blue) on synthesis of enzymes involved in glycolysis, gluconeogenesis, and the TCA cycle. A green asterisk and bold letters indicate direct regulation by CsrA ( 106 ). Anabolic pathways directing synthesis of glycogen, UDP-sugars, and the biofilm compound PGA are also shown.
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FIGURE 3

Posttranscriptional regulation of central carbon metabolic pathways in . Effects of sRNAs (depicted in red) and of the RNA-binding protein CsrA (blue) on synthesis of enzymes involved in glycolysis, gluconeogenesis, and the TCA cycle. A green asterisk and bold letters indicate direct regulation by CsrA ( 106 ). Anabolic pathways directing synthesis of glycogen, UDP-sugars, and the biofilm compound PGA are also shown.

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FIGURE 4
Model of the interconnection of the CsrA system with central carbon metabolism. Decoy sRNAs CsrB and CsrC regulate CsrA activity by sequestering the protein from its target mRNAs. CsrA indirectly activates transcription, creating a negative feedback loop. In fast-growing cells, when CsrB/C levels are low, CsrA activates glycolytic genes and represses the TCA cycle, gluconeogenesis, and glycogen synthesis. Metabolism of glycolytic carbon sources causes accumulation of FBP, which activates pyruvate kinase, thereby reducing the PEP/pyruvate ratio. Intake of PTS substrates and a low PEP/pyruvate ratio trigger dephosphorylation of EIIA, leading to activation of CsrD, which triggers degradation of CsrB/CsrC by RNase E. Upon accumulation of short carboxylic acids (R-COOH) as metabolic end products, expression of / is induced by the BarA/UvrY TCS. Deceleration of glycolytic activity elevates the PEP/pyruvate level and increases EIIA phosphorylation, leading to stabilization of CsrB/CsrC and titration of CsrA. EIIA∼P stimulates adenylate cyclase CyaA, which converts ATP to cAMP. The cAMP-CRP complex inhibits transcription of . Involvement of EIIA in regulation of CsrB/CsrC synthesis as well as decay allows integration of further cues.
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Image of FIGURE 4
FIGURE 4

Model of the interconnection of the CsrA system with central carbon metabolism. Decoy sRNAs CsrB and CsrC regulate CsrA activity by sequestering the protein from its target mRNAs. CsrA indirectly activates transcription, creating a negative feedback loop. In fast-growing cells, when CsrB/C levels are low, CsrA activates glycolytic genes and represses the TCA cycle, gluconeogenesis, and glycogen synthesis. Metabolism of glycolytic carbon sources causes accumulation of FBP, which activates pyruvate kinase, thereby reducing the PEP/pyruvate ratio. Intake of PTS substrates and a low PEP/pyruvate ratio trigger dephosphorylation of EIIA, leading to activation of CsrD, which triggers degradation of CsrB/CsrC by RNase E. Upon accumulation of short carboxylic acids (R-COOH) as metabolic end products, expression of / is induced by the BarA/UvrY TCS. Deceleration of glycolytic activity elevates the PEP/pyruvate level and increases EIIA phosphorylation, leading to stabilization of CsrB/CsrC and titration of CsrA. EIIA∼P stimulates adenylate cyclase CyaA, which converts ATP to cAMP. The cAMP-CRP complex inhibits transcription of . Involvement of EIIA in regulation of CsrB/CsrC synthesis as well as decay allows integration of further cues.

Source: microbiolspec March 2018 vol. 6 no. 2 doi:10.1128/microbiolspec.RWR-0013-2017
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FIGURE 5
Role of RNase E adaptor protein RapZ in feedback regulation of GlmS synthesis in . When GlcN6P is plentiful in the cell, RapZ prevents upregulation by targeting its activating sRNA GlmZ to cleavage by RNase E. Within the tripartite complex formed, the sRNA is envisioned to be sandwiched between the tetrameric RapZ protein and the N-terminal domain (NTD) of RNase E, which also forms a tetramer ( 168 ). Processing results in functional inactivation of GlmZ and subsequent decline in GlmS levels. Conversely, under GlcN6P depletion, RapZ is predominantly sequestered in complexes with the homologous sRNA GlmY, whose levels increase under this condition. Consequently, GlmZ remains in its active full-length form and stimulates expression. Higher levels of GlmS replenish GlcN6P levels in the cell. Whether RapZ has an active role in sensing GlcN6P via direct binding of the metabolite within its C-terminal domain (CTD) is currently under investigation. The unusual tetrameric structure of RapZ is schematically depicted in the box in the upper left. Each monomer is represented by one color and consists of two globular domains, NTD and CTD, connected via flexible linkers. Three distinct surfaces involved in self-interaction can be discerned: CTD-CTD, NTD-NTD, as well as CTD-NTD ( 168 ).
microbiolspec/6/2/RWR-0013-2017-fig5_thmb.gif
microbiolspec/6/2/RWR-0013-2017-fig5.gif
Image of FIGURE 5
FIGURE 5

Role of RNase E adaptor protein RapZ in feedback regulation of GlmS synthesis in . When GlcN6P is plentiful in the cell, RapZ prevents upregulation by targeting its activating sRNA GlmZ to cleavage by RNase E. Within the tripartite complex formed, the sRNA is envisioned to be sandwiched between the tetrameric RapZ protein and the N-terminal domain (NTD) of RNase E, which also forms a tetramer ( 168 ). Processing results in functional inactivation of GlmZ and subsequent decline in GlmS levels. Conversely, under GlcN6P depletion, RapZ is predominantly sequestered in complexes with the homologous sRNA GlmY, whose levels increase under this condition. Consequently, GlmZ remains in its active full-length form and stimulates expression. Higher levels of GlmS replenish GlcN6P levels in the cell. Whether RapZ has an active role in sensing GlcN6P via direct binding of the metabolite within its C-terminal domain (CTD) is currently under investigation. The unusual tetrameric structure of RapZ is schematically depicted in the box in the upper left. Each monomer is represented by one color and consists of two globular domains, NTD and CTD, connected via flexible linkers. Three distinct surfaces involved in self-interaction can be discerned: CTD-CTD, NTD-NTD, as well as CTD-NTD ( 168 ).

Source: microbiolspec March 2018 vol. 6 no. 2 doi:10.1128/microbiolspec.RWR-0013-2017
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