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  • 1.
    Akar, Roya
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fink, Matthias J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regulation of the ECF sigma factor SigT by Lon-mediated proteolysisManuscript (preprint) (Other academic)
    Abstract [en]

    The Lon protease is widely conserved in both prokaryotic and eukaryotic species in which it fulfils important regulatory functions. Nevertheless, the number of identified Lon substrates is limited in most organisms and the precise role of Lon in regulating these proteins poorly understood. Previous quantitative proteomics data classified the general stress response sigma factor SigT as a promising putative Lon substrate in the dimorphic bacterium Caulobacter crescentus. Here, we confirm that SigT abundance is directly regulated by Lon. We show that downregulation of SigT levels during recovery from sucrose-induced osmotic stress is delayed in the absence of Lon, while its upregulation at the onset of stress functions normally. Furthermore, the presence of the Lon regulator LarA enhances Lon-mediated degradation of SigT in vitro and reduces SigT levels in vivo indicating a role of LarA in regulating Lon-mediated degradation of SigT. Together, our results emphasize the importance of Lon during the recovery phase following stress exposure by adjusting the concentration of the general stress response regulator SigT.

  • 2.
    Akar, Roya
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fink, Matthias J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Omnus, Deike J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regulation of the general stress response sigma factor σT by Lon-mediated proteolysis2023In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 205, no 11Article in journal (Refereed)
    Abstract [en]

    The Lon protease is widely conserved in both prokaryotic and eukaryotic organisms and fulfills important regulatory functions. Nevertheless, the number of identified Lon substrates is limited in most organisms, and the precise role of Lon in regulating these proteins is poorly understood. Here, we describe the α-proteobacterial general stress response sigma factor σT as a novel Lon substrate in Caulobacter crescentus. Based on previously published quantitative proteomics data, we find σT to be a promising putative Lon substrate and confirm a direct role of Lon in degrading σT. We show that Lon contributes to the downregulation of σT abundance under optimal conditions and during recovery from sucrose-induced osmotic stress. Furthermore, the presence of the Lon activity regulator LarA enhances Lon-mediated degradation of σT in vitro and reduces σT levels in vivo indicating a role of LarA in modulating Lon-mediated degradation of σT. Together, our results highlight the importance of Lon during the recovery phase following stress exposure by adjusting the concentrations of critical regulators of stress responses.

  • 3.
    Felletti, Michele
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Omnus, Deike J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Regulation of the replication initiator DnaA in Caulobacter crescentus2019In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, no 7, p. 697-705Article, review/survey (Refereed)
    Abstract [en]

    The decision to initiate DNA replication is a critical step in the cell cycle of all organisms. In nearly all bacteria, replication initiation requires the activity of the conserved replication initiation protein DnaA. Due to its central role in cell cycle progression, DnaA activity must be precisely regulated. This review summarizes the current state of DnaA regulation in the asymmetrically dividing alpha-proteobacterium Caulobacter crescentus, an important model for bacterial cell cycle studies. Mechanisms will be discussed that regulate DnaA activity and abundance under optimal conditions and in coordination with the asymmetric Caulobacter cell cycle. Furthermore, we highlight recent findings of how regulated DnaA synthesis and degradation collaborate to adjust DnaA abundance under stress conditions. The mechanisms described provide important examples of how DNA replication is regulated in an a-proteobacterium and thus represent an important starting point for the study of DNA replication in many other bacteria. This article is part of a Special Issue entitled: Dynamic gene expression, edited by Prof. Patrick Viollier.

  • 4.
    Felletti, Michele
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Romilly, Cedric
    Wagner, E. Gerhart H.
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    A nascent polypeptide sequence modulates DnaA translation elongation in response to nutrient availability2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e71611Article in journal (Refereed)
    Abstract [en]

    The ability to regulate DNA replication initiation in response to changing nutrient conditions is an important feature of most cell types. In bacteria, DNA replication is triggered by the initiator protein DnaA, which has long been suggested to respond to nutritional changes; nevertheless, the underlying mechanisms remain poorly understood. Here, we report a novel mechanism that adjusts DnaA synthesis in response to nutrient availability in Caulobacter crescentus. By performing a detailed biochemical and genetic analysis of the dnaA mRNA, we identified a sequence downstream of the dnaA start codon that inhibits DnaA translation elongation upon carbon exhaustion. Our data show that the corresponding peptide sequence, but not the mRNA secondary structure or the codon choice, is critical for this response, suggesting that specific amino acids in the growing DnaA nascent chain tune translational efficiency. Our study provides new insights into DnaA regulation and highlights the importance of translation elongation as a regulatory target. We propose that translation regulation by nascent chain sequences, like the one described, might constitute a general strategy for modulating the synthesis rate of specific proteins under changing conditions.

  • 5.
    Hallgren, Joel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nutritional control of bacterial DNA replication2024In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 77, article id 102403Article, review/survey (Refereed)
    Abstract [en]

    All cells must ensure precise regulation of DNA replication initiation in coordination with growth rate and in response to nutrient availability. According to a long-standing model, DNA replication initiation is tightly coupled to cell mass increase in bacteria. Despite controversies regarding this model, recent studies have provided additional support of this idea. The exact molecular mechanisms linking cell growth with DNA replication under different nutrient conditions remain elusive. However, recent studies in Caulobacter crescentus and Escherichia coli have provided insights into the regulation of DNA replication initiation in response to starvation. These mechanisms include the starvation-dependent regulation of DnaA abundance as well as mechanisms involving the small signaling molecule (p)ppGpp. In this review, we discuss these mechanisms in the context of previous findings. We highlight species-dependent similarities and differences and consider the precise growth conditions, in which the different mechanisms are active.

  • 6.
    Hallgren, Joel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Koonce, Kira
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Felletti, Michele
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mortier, Julien
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Turco, Eloisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Phosphate starvation decouples cell differentiation from DNA replication control in the dimorphic bacterium Caulobacter crescentus2023In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 19, no 11, article id e1010882Article in journal (Refereed)
    Abstract [en]

    Upon nutrient depletion, bacteria stop proliferating and undergo physiological and morphological changes to ensure their survival. Yet, how these processes are coordinated in response to distinct starvation conditions is poorly understood. Here we compare the cellular responses of Caulobacter crescentus to carbon (C), nitrogen (N) and phosphorus (P) starvation conditions. We find that DNA replication initiation and abundance of the replication initiator DnaA are, under all three starvation conditions, regulated by a common mechanism involving the inhibition of DnaA translation. By contrast, cell differentiation from a motile swarmer cell to a sessile stalked cell is regulated differently under the three starvation conditions. During C and N starvation, production of the signaling molecules (p)ppGpp is required to arrest cell development in the motile swarmer stage. By contrast, our data suggest that low (p)ppGpp levels under P starvation allow P-starved swarmer cells to differentiate into sessile stalked cells. Further, we show that limited DnaA availability, and consequently absence of DNA replication initiation, is the main reason that prevents P-starved stalked cells from completing the cell cycle. Together, our findings demonstrate that Ccrescentus decouples cell differentiation from DNA replication initiation under certain starvation conditions, two otherwise intimately coupled processes. We hypothesize that arresting the developmental program either as motile swarmer cells or as sessile stalked cells improves the chances of survival of Ccrescentus during the different starvation conditions.

  • 7.
    Heinrich, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Leslie, David J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Morlock, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bertilsson, Stefan
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Molecular Basis and Ecological Relevance of Caulobacter Cell Filamentation in Freshwater Habitats2019In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, no 4, article id e01557-19Article in journal (Refereed)
    Abstract [en]

    All living cells are characterized by certain cell shapes and sizes. Many bacteria can change these properties depending on the growth conditions. The underlying mechanisms and the ecological relevance of changing cell shape and size remain unclear in most cases. One bacterium that undergoes extensive shape-shifting in response to changing growth conditions is the freshwater bacterium Caulobacter crescentus. When incubated for an extended time in stationary phase, a subpopulation of C. crescentus forms viable filamentous cells with a helical shape. Here, we demonstrated that this stationary-phase-induced filamentation results from downregulation of most critical cell cycle regulators and a consequent block of DNA replication and cell division while cell growth and metabolism continue. Our data indicate that this response is triggered by a combination of three stresses caused by prolonged growth in complex medium, namely, the depletion of phosphate, alkaline pH, and an excess of ammonium. We found that these conditions are experienced in the summer months during algal blooms near the surface in freshwater lakes, a natural habitat of C. crescentus, suggesting that filamentous growth is a common response of C. crescentus to its environment. Finally, we demonstrate that when grown in a biofilm, the filamentous cells can reach beyond the surface of the biofilm and potentially access nutrients or release progeny. Altogether, our work highlights the ability of bacteria to alter their morphology and suggests how this behavior might enable adaptation to changing environments.

  • 8.
    Heinrich, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    Sobetzko, Patrick
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit2016In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 12, article id e1006522Article in journal (Refereed)
    Abstract [en]

    The bacterial cell cycle has been extensively studied under standard growth conditions. How it is modulated in response to environmental changes remains poorly understood. Here, we demonstrate that the freshwater bacterium Caulobacter crescentus blocks cell division and grows to filamentous cells in response to stress conditions affecting the cell membrane. Our data suggest that stress switches the membrane-bound cell cycle kinase CckA to its phosphatase mode, leading to the rapid dephosphorylation, inactivation and proteolysis of the master cell cycle regulator CtrA. The clearance of CtrA results in downregulation of division and morphogenesis genes and consequently a cell division block. Upon shift to non-stress conditions, cells quickly restart cell division and return to normal cell size. Our data indicate that the temporary inhibition of cell division through the regulated inactivation of CtrA constitutes a growth advantage under stress. Taken together, our work reveals a new mechanism that allows bacteria to alter their mode of proliferation in response to environmental cues by controlling the activity of a master cell cycle transcription factor. Furthermore, our results highlight the role of a bifunctional kinase in this process that integrates the cell cycle with environmental information.

  • 9.
    Leslie, David J.
    et al.
    Philipps University Marburg, Germany; Max Planck Institute for Terrestrial Microbiology, Germany.
    Heinen, Christian
    Philipps University Marburg, Germany, Max Planck Institute for Terrestrial Microbiology, Germany.
    Schramm, Frederic D.
    Philipps University Marburg, Germany.
    Thüring, Marietta
    Philipps University Marburg, Germany.
    Aakre, Christopher D.
    Massachusetts Institute of Technology, United States of America.
    Murray, Sean M.
    Philipps University Marburg, Germany; Max Planck Institute for Terrestrial Microbiology, Germany.
    Laub, Michael T.
    Massachusetts Institute of Technology, United States of America.
    Jonas, Kristina
    Philipps University Marburg, Germany.
    Nutritional Control of DNA Replication Initiation through the Proteolysis and Regulated Translation of DnaA2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 7, article id e1005342Article in journal (Refereed)
    Abstract [en]

    Bacteria can arrest their own growth and proliferation upon nutrient depletion and under various stressful conditions to ensure their survival. However, the molecular mechanisms responsible for suppressing growth and arresting the cell cycle under such conditions remain incompletely understood. Here, we identify post-transcriptional mechanisms that help enforce a cell-cycle arrest in Caulobacter crescentus following nutrient limitation and during entry into stationary phase by limiting the accumulation of DnaA, the conserved replication initiator protein. DnaA is rapidly degraded by the Lon protease following nutrient limitation. However, the rate of DnaA degradation is not significantly altered by changes in nutrient availability. Instead, we demonstrate that decreased nutrient availability downregulates dnaA translation by a mechanism involving the 5' untranslated leader region of the dnaA transcript; Lon-dependent proteolysis of DnaA then outpaces synthesis, leading to the elimination of DnaA and the arrest of DNA replication. Our results demonstrate how regulated translation and constitutive degradation provide cells a means of precisely and rapidly modulating the concentration of key regulatory proteins in response to environmental inputs.

  • 10.
    Leslie, David J.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Thüring, Marietta
    Wongwattanarat, Sasipa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Regulation of DnaA and DNA replication at the onset of stationary phase in E. coliManuscript (preprint) (Other academic)
  • 11. Li, Fengyang
    et al.
    Cao, Lianying
    Bähre, Heike
    Kim, Soo-Kyoung
    Schroeder, Kristen
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Koonce, Kira
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mekonnen, Solomon A.
    Mohanty, Soumitra
    Bai, Fengwu
    Brauner, Annelie
    Lee, Vincent T.
    Rohde, Manfred
    Römling, Ute
    Patatin-like phospholipase CapV in Escherichia coli-morphological and physiological effects of one amino acid substitution2022In: npj Biofilms and Microbiomes, E-ISSN 2055-5008, Vol. 8, no 1, article id 39Article in journal (Refereed)
    Abstract [en]

    In rod-shaped bacteria, morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that overexpression of the patatin-like phospholipase variant CapV(Q329R), but not CapV, causes pronounced sulA-independent pyridoxine-inhibited cell filamentation in the Escherichia coli K-12-derivative MG1655 associated with restriction of flagella production and swimming motility. Conserved amino acids in canonical patatin-like phospholipase A motifs, but not the nucleophilic serine, are required to mediate CapV(Q329R) phenotypes. Furthermore, CapV(Q329R) production substantially alters the lipidome and colony morphotype including rdar biofilm formation with modulation of the production of the biofilm activator CsgD, and affects additional bacterial traits such as the efficiency of phage infection and antimicrobial susceptibility. Moreover, genetically diverse commensal and pathogenic E. coli strains and Salmonella typhimurium responded with cell filamentation and modulation in colony morphotype formation to CapV(Q329R) expression. In conclusion, this work identifies the CapV variant CapV(Q329R) as a pleiotropic regulator, emphasizes a scaffold function for patatin-like phospholipases, and highlights the impact of the substitution of a single conserved amino acid for protein functionality and alteration of host physiology.

  • 12.
    Omnus, Deike J.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fink, Matthias J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kallazhi, Aswathy
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Xandri Zaragoza, Maria
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The heat shock protein LarA activates the Lon protease at the onset of proteotoxic stressManuscript (preprint) (Other academic)
    Abstract [en]

    The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that LarA is regulated by Lon itself, which is critical to prevent toxic overactivation of Lon. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand at the onset of protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.

  • 13.
    Omnus, Deike J.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Fink, Matthias J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Kallazhi, Aswathy
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Xandri Zaragoza, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Leppert, Axel
    Landreh, Michael
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The heat shock protein LarA activates the Lon protease in response to proteotoxic stress2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 7636Article in journal (Refereed)
    Abstract [en]

    The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that high levels of LarA cause growth inhibition in a Lon-dependent manner and that Lon-mediated degradation of LarA itself ensures low LarA levels in the absence of stress. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand in response to protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.

  • 14. Omnus, Deike J.
    et al.
    Fink, Matthias J.
    Szwedo, Klaudia
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Lon protease temporally restricts polar cell differentiation events during the Caulobacter cell cycle2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e73875Article in journal (Refereed)
    Abstract [en]

    The highly conserved protease Lon has important regulatory and protein quality control functions in cells from the three domains of life. Despite many years of research on Lon, only a few specific protein substrates are known in most organisms. Here, we used a quantitative proteomics approach to identify novel substrates of Lon in the dimorphic bacterium Caulobacter crescentus. We focused our study on proteins involved in polar cell differentiation and investigated the developmental regulator StaR and the flagella hook length regulator FliK as specific Lon substrates in detail. We show that Lon recognizes these proteins at their C-termini, and that Lon-dependent degradation ensures their temporally restricted accumulation in the cell cycle phase when their function is needed. Disruption of this precise temporal regulation of StaR and FliK levels in a Delta lon mutant contributes to defects in stalk biogenesis and motility, respectively, revealing a critical role of Lon in coordinating developmental processes with cell cycle progression. Our work underscores the importance of Lon in the regulation of complex temporally controlled processes by adjusting the concentrations of critical regulatory proteins. Furthermore, this study includes the first characterization of FliK in C. crescentus and uncovers a dual role of the C-terminal amino acids of FliK in protein function and degradation.

  • 15.
    Schramm, Frederic D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    Heinrich, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    Thüring, Marietta
    Bernhardt, Jörg
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Philipps University Marburg, Germany.
    An essential regulatory function of the DnaK chaperone dictates the decision between proliferation and maintenance in Caulobacter crescentus2017In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 12, article id e1007148Article in journal (Refereed)
    Abstract [en]

    Hsp70 chaperones are well known for their important functions in maintaining protein homeostasis during thermal stress conditions. In many bacteria the Hsp70 homolog DnaK is also required for growth in the absence of stress. The molecular reasons underlying Hsp70 essentiality remain in most cases unclear. Here, we demonstrate that DnaK is essential in the alpha-proteobacterium Caulobacter crescentus due to its regulatory function in gene expression. Using a suppressor screen we identified mutations that allow growth in the absence of DnaK. All mutations reduced the activity of the heat shock sigma factor sigma(32) , demonstrating that the DnaK-dependent inactivation of sigma(32) is a growth requirement. While most mutations occurred in the rpoH gene encoding sigma(32) , we also identified mutations affecting sigma(32) activity or stability in trans, providing important new insight into the regulatory mechanisms controlling sigma(32) activity. Most notably, we describe a mutation in the ATP dependent protease HslUV that induces rapid degradation of sigma(32) , and a mutation leading to increased levels of the house keeping sigma(70) that outcompete sigma(32) for binding to the RNA polymerase. We demonstrate that sigma(32) inhibits growth and that its unrestrained activity leads to an extensive reprogramming of global gene expression, resulting in upregulation of repair and maintenance functions and downregulation of the growth-promoting functions of protein translation, DNA replication and certain metabolic processes. While this re-allocation from proliferative to maintenance functions could provide an advantage during heat stress, it leads to growth defects under favorable conditions. We conclude that Caulobacter has coopted the DnaK chaperone system as an essential regulator of gene expression under conditions when its folding activity is dispensable.

  • 16.
    Schramm, Frederic D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schroeder, Kristen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Alvelid, Jonatan
    Testa, Ilaria
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Growth‐driven displacement of protein aggregates along the cell length ensures partitioning to both daughter cells in Caulobacter crescentus2019In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 111, no 6, p. 1430-1448Article in journal (Refereed)
    Abstract [en]

    All living cells must cope with protein aggregation, which occurs as a result of experiencing stress. In previously studied bacteria, aggregated protein collects at the cell poles and is retained throughout consecutive cell divisions only in old pole‐inheriting daughter cells, resulting in aggregation‐free progeny within a few generations. In this study we describe the in vivo kinetics of aggregate formation and elimination following heat and antibiotic stress in the asymmetrically dividing bacterium Caulobacter crescentus. Unexpectedly, in this bacterium protein aggregates form as multiple distributed foci located throughout the cell volume. Time‐lapse microscopy revealed that under moderate stress, the majority of these protein aggregates are short‐lived and rapidly dissolved by the major chaperone DnaK and the disaggregase ClpB. Severe stress or genetic perturbation of the protein quality control machinery induces the formation of long‐lived aggregates. Importantly, the majority of persistent aggregates neither collect at the cell poles nor are they partitioned to only one daughter cell type. Instead, we show that aggregates are distributed to both daughter cells in the same ratio at each division, which is driven by the continuous elongation of the growing mother cell. Therefore, our study has revealed a new pattern of protein aggregate inheritance in bacteria.

  • 17.
    Schramm, Frederic D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schroeder, Kristen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Protein aggregation in bacteria2020In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 44, no 1, p. 54-72Article, review/survey (Refereed)
    Abstract [en]

    Protein aggregation occurs as a consequence of perturbations in protein homeostasis that can be triggered by environmental and cellular stresses. The accumulation of protein aggregates has been associated with aging and other pathologies in eukaryotes, and in bacteria with changes in growth rate, stress resistance and virulence. Numerous past studies, mostly performed in Escherichia coli, have led to a detailed understanding of the functions of the bacterial protein quality control machinery in preventing and reversing protein aggregation. However, more recent research points toward unexpected diversity in how phylogenetically different bacteria utilize components of this machinery to cope with protein aggregation. Furthermore, how persistent protein aggregates localize and are passed on to progeny during cell division and how their presence impacts reproduction and the fitness of bacterial populations remains a controversial field of research. Finally, although protein aggregation is generally seen as a symptom of stress, recent work suggests that aggregation of specific proteins under certain conditions can regulate gene expression and cellular resource allocation. This review discusses recent advances in understanding the consequences of protein aggregation and how this process is dealt with in bacteria, with focus on highlighting the differences and similarities observed between phylogenetically different groups of bacteria.

  • 18.
    Schroeder, Kristen
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Furniss, R. Christopher D.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chaperonin folding protects energy metabolism via TCA cycle and respiratory chain proteins in the obligate aerobe Caulobacter crescentusManuscript (preprint) (Other academic)
  • 19. Schroeder, Kristen
    et al.
    Heinrich, Kristina
    Neuwirth, Ines
    Jonas, Kristina
    The chaperonin GroESL facilitates Caulobacter crescentus cell division by supporting the functions of the Z-ring regulators FtsA and FzlAIn: mBio, ISSN 2161-2129, E-ISSN 2150-7511Article in journal (Refereed)
  • 20.
    Schroeder, Kristen
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Heinrich, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neuwirth, Ines
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    The Chaperonin GroESL Facilitates Caulobacter crescentus Cell Division by Supporting the Functions of the Z-Ring Regulators FtsA and FzlA2021In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 12, no 3, article id e03564-20Article in journal (Refereed)
    Abstract [en]

    The highly conserved chaperonin GroESL performs a crucial role in protein folding; however, the essential cellular pathways that rely on this chaperone are underexplored. Loss of GroESL leads to severe septation defects in diverse bacteria, suggesting the folding function of GroESL may be integrated with the bacterial cell cycle at the point of cell division. Here, we describe new connections between GroESL and the bacterial cell cycle using the model organism Caulobacter crescentus. Using a proteomics approach, we identify candidate GroESL client proteins that become insoluble or are degraded specifically when GroESL folding is insufficient, revealing several essential proteins that participate in cell division and peptidoglycan biosynthesis. We demonstrate that other cell cycle events, such as DNA replication and chromosome segregation, are able to continue when GroESL folding is insuffi- cient. We further find that deficiency of two FtsZ-interacting proteins, the bacterial actin homologue FtsA and the constriction regulator FzlA, mediate the GroESL-dependent block in cell division. Our data show that sufficient GroESL is required to maintain normal dynamics of the FtsZ scaffold and divisome functionality in C. crescentus. In addition to supporting divisome function, we show that GroESL is required to maintain the flow of peptidoglycan precursors into the growing cell wall. Linking a chaperone to cell division may be a conserved way to coordinate environmental and internal cues that signal when it is safe to divide. IMPORTANCE All organisms depend on mechanisms that protect proteins from misfolding and aggregation. GroESL is a highly conserved molecular chaperone that functions to prevent protein aggregation in organisms ranging from bacteria to humans. Despite detailed biochemical understanding of GroESL function, the in vivo pathways that strictly depend on this chaperone remain poorly defined in most species. This study provides new insights into how GroESL is linked to the bacterial cell division machinery, a crucial target of current and future antimicrobial agents. We identify a functional interaction between GroESL and the cell division proteins FzlA and FtsA, which modulate Z-ring function. FtsA is a conserved bacterial actin homologue, suggesting that as in eukaryotes, some bacteria exhibit a connection between cytoskeletal actin proteins and chaperonins. Our work further defines how GroESL is integrated with cell wall synthesis and illustrates how highly conserved folding machines ensure the functioning of fundamental cellular processes during stress.

  • 21.
    Schroeder, Kristen
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Protein Quality Control Network in Caulobacter crescentus2021In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 8, article id 682967Article, review/survey (Refereed)
    Abstract [en]

    The asymmetric life cycle of Caulobacter crescentus has provided a model in which to study how protein quality control (PQC) networks interface with cell cycle and developmental processes, and how the functions of these systems change during exposure to stress. As in most bacteria, the PQC network of Caulobacter contains highly conserved ATP-dependent chaperones and proteases as well as more specialized holdases. During growth in optimal conditions, these systems support a regulated circuit of protein synthesis and degradation that drives cell differentiation and cell cycle progression. When stress conditions threaten the proteome, most components of the Caulobacter proteostasis network are upregulated and switch to survival functions that prevent, revert, and remove protein damage, while simultaneously pausing the cell cycle in order to regain protein homeostasis. The specialized physiology of Caulobacter influences how it copes with proteotoxic stress, such as in the global management of damaged proteins during recovery as well as in cell type-specific stress responses. Our mini-review highlights the discoveries that have been made in how Caulobacter utilizes its PQC network for regulating its life cycle under optimal and proteotoxic stress conditions, and discusses open research questions in this model.

  • 22.
    Wassing, Gabriela M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lidberg, Kenny
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sigurlásdóttir, Sara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Frey, Jonas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Schroeder, Kristen
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ilehag, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindås, Ann-Christin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    DNA Blocks the Lethal Effect of Human Beta-Defensin 2 Against Neisseria meningitidis2021In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 697232Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is a gram-negative bacterium that often asymptomatically colonizes the human nasopharyngeal tract. These bacteria cross the epithelial barrier can cause life-threatening sepsis and/or meningitis. Antimicrobial peptides are one of the first lines of defense against invading bacterial pathogens. Human beta-defensin 2 (hBD2) is an antimicrobial peptide with broad antibacterial activity, although its mechanism of action is poorly understood. Here, we investigated the effect of hBD2 on N. meningitidis. We showed that hBD2 binds to and kills actively growing meningococcal cells. The lethal effect was evident after 2 h incubation with the peptide, which suggests a slow killing mechanism. Further, the membrane integrity was not changed during hBD2 treatment. Incubation with lethal doses of hBD2 decreased the presence of diplococci; the number and size of bacterial microcolonies/aggregates remained constant, indicating that planktonic bacteria may be more susceptible to the peptide. Meningococcal DNA bound hBD2 in mobility shift assays and inhibited the lethal effect of hBD2 in a dose-dependent manner both in suspension and biofilms, supporting the interaction between hBD2 and DNA. Taken together, the ability of meningococcal DNA to bind hBD2 opens the possibility that extracellular DNA due to bacterial lysis may be a means of N. meningitidis to evade immune defenses.

  • 23.
    Wassing, Gabriela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sigurlásdóttir, Sara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Schroeder, Kristen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ilehag, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindås, Ann-Christin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonas, Kristina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Meningococcal DNA binds to human beta-defensin 2 and blocks its lethal effect against the bacteriaManuscript (preprint) (Other academic)
1 - 23 of 23
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