Search bioRxiv⌕ Search

Biology subjects

Le Bars, R.

Publications and source records attributed to Le Bars, R..

9 recordsLinked to original sources

Distinct spatial organisation of Rho and RNA Polymerase in Salmonella cells

Rho is a conserved, ATP-dependent RNA translocase that terminates transcription at hundreds of sites across bacterial genomes. Although the molecular mechanism of Rho-dependent termination is well characterized, its spatial interplay with RNA polymerase (RNAP) within bacterial cells remains elusive. To address this question, we constructed intragenic, in-frame fusions inserting mCherry or sfGFP 48 amino acid residues downstream of the N-terminus of Rho in Salmonella. Strikingly, mCherry - but not sfGFP - renders the first 48 residues of Rho dispensable. Rho{Delta}48::mCherry is viable in single copy and exhibits wild-type termination activity in vitro, whereas the full-length Rho::sfGFP fusion, although viable, slows growth and shows strongly reduced activity. Structured illumination microscopy (SIM) revealed that, despite these functional differences, both constructs exhibit similar localisation patterns relative to fluorescently tagged RNAP in single cells. During exponential growth, both Rho and RNAP form discrete clusters, but with markedly distinct spatial organisations: RNAP clusters associate with the nucleoid, whereas Rho is distributed throughout the cell body. This spatial partitioning persists in stationary phase, where RNAP becomes diffusely associated with a compacted nucleoid while Rho accumulates at the cell periphery. The widespread distribution of Rho at cytoplasmic locations is unexpected and suggests participation in cellular functions beyond its canonical role in transcription termination.

microbiology↗

Localised activity of reverse gyrase at gene regulatory elements

DNA topoisomerases are essential enzymes found in all cells, where they regulate DNA supercoiling. Reverse gyrase (RG) is a unique type of topoisomerase that introduces positive supercoils into DNA and appears exclusively in hyperthermophiles where it was proposed to play a key, yet still elusive, role. Here, we investigate RG activity in the hyperthermophilic archaeon Thermococcus kodakarensis at 85{degrees}C, its optimal growth temperature, using genetics and functional genomics assays. Deletion of RG led to a loss of positive supercoiling in plasmid DNA and the reduced dynamic range of transcription, without affecting histone occupancy. To investigate the effects of RG loss on the topology of chromosomal DNA, we established a psoralen photobinding assay (TMP-seq) in T. kodakarensis under native growth conditions. TMP enrichment patterns were consistent with the twin-domain model of transcription and further revealed that promoters of expressed transcription units are, on average, underwound. TMP-seq profiles in an RG deletion strain revealed that promoters are hotspots for RG activity, consistent with RG acting on hyper-negatively supercoiled substrates. We propose that RG acts not as a global modulator of supercoiling, but as a local genome guardian, selectively stabilising vulnerable regulatory regions to ensure a delicate balance between DNA accessibility and integrity under extremely high temperatures.

microbiology↗

Bacterial chromatin remodeling associated with transcription-induced domains at pathogenicity islands

The nucleoid-associated protein H-NS is a bacterial xenogeneic silencer responsible for preventing costly expression of genes acquired through horizontal gene transfer. H-NS silences several Salmonella Pathogenicity Islands (SPIs) essential for host infection. The stochastic expression of SPI-1 is required for invasion of host epithelial cells but complicates investigation of factors involved in SPI-1 chromatin structure and regulation. We performed functional genomics on sorted Salmonella populations expressing SPI-1 or not, to characterize how SPI-1 activation affects chromatin composition, DNA conformation, gene expression and SPI-1 subcellular localization. High H-NS occupancy co-exists with low spurious transcriptional activity and low RNA polymerase occupancy at silent SPIs. Upon SPI-1 activation, remodeling of H-NS occupancy defines a new chromatin landscape, which together with the master SPI-1 regulator HilD, facilitates transcription of SPI-1 genes. SPI-1 activation promotes formation of Transcription Induced Domains accompanied by repositioning SPI-1 close to the nucleoid periphery. We present a model for tightly regulated chromatin remodeling that minimizes the cost of pathogenicity island activation

microbiology↗

KIF2C-induced nuclear condensation concentrates PLK1 and phosphorylated BRCA2 at the kinetochore microtubules in mitosis

During mitosis, the human microtubule depolymerase KIF2C increases the turnover of kinetochore-microtubule attachments. This facilitates the correction of attachment errors. Moreover, BRCA2 phosphorylated at Thr207 by PLK1 (BRCA2-pT207) assembles a complex including PLK1, PP2A and BUBR1 that contributes to the stability of the kinetochore-microtubule attachments. PLK1, together with Aurora B, critically regulate the accurate segregation of chromosomes. Here we demonstrate that KIF2C contains an N-terminal domain that binds directly to several phosphorylated peptides, including BRCA2-pT207. Using an optogenetic platform, we reveal that KIF2C assembles into membrane-less compartments or biomolecular condensates that are located next to microtubules. We provide evidence that condensate assembly depends on the presence of the newly defined N-terminal phospho-binding domain of KIF2C and on the kinase activities of Aurora B and PLK1. Moreover, KIF2C condensates concentrate active PLK1 and colocalize with BRCA2-pT207. We propose that, because of its phospho-dependent binding and oligomerization capacities, KIF2C forms biomolecular condensates that partition PLK1 and locally amplify its kinase activity during mitosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/589357v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@3ff5bforg.highwire.dtl.DTLVardef@11efbdcorg.highwire.dtl.DTLVardef@1295118org.highwire.dtl.DTLVardef@18b3dd3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

The Bacterial Replicative Helicase Loader DciA is a DNA Condenser.

The loading of the bacterial replicative helicase is an essential step for genome replication and depends on the assistance of accessory proteins. Several of these proteins have been identified across the bacterial phyla. DciA is the most common loading protein in bacteria, yet the one whose mechanism is the least understood. We have previously shown that VcDciA from Vibrio cholerae, composed of a globular KH-like domain followed by an unfolded extension, has a strong affinity for DNA. Here, we characterized the droplets formed by VcDciA upon interaction with a short single-stranded substrate. We demonstrate the fluidity of these droplets using light microscopy and address their network organization through electron microscopy, thereby bridging events to conclude on a liquid-liquid phase separation behavior. Additionally, we observe the recruitment of VcDnaB inside the VcDciA-DNA droplets. We show that DnaC from Escherichia coli is also competent to form these condensate structures in the presence of ssDNA. Our data open up possibilities for the involvement of DciA in the formation of non-membrane compartments within the bacterium, facilitating the assembly of replication players with the chromosomal DNA.

biochemistry↗

Sinorhizobium meliloti FcrX coordinates cell cycle and division during free-living growth and symbiosis

Sinorhizobium meliloti is a soil bacterium that establishes a symbiosis within root nodules of legumes (Medicago sativa, for example) where it fixes atmospheric nitrogen into ammonia and obtains in return carbon sources and other nutrients. In this symbiosis, S. meliloti undergoes a drastic cellular change leading to a terminal differentiated form (called bacteroid) characterized by genome endoreduplication, increase of cell size and high membrane permeability. The bacterial cell cycle (mis)regulation is at the heart of this differentiation process. In free-living cells, the master regulator CtrA ensures the progression of cell cycle by activating cell division (controlled by the tubulin-like protein FtsZ) and simultaneously inhibiting supernumerary DNA replication, while on the other hand the downregulation of CtrA and FtsZ is essential for bacteroid differentiation during symbiosis, preventing endosymbiont division and permitting genome endoreduplication. Little is known in S. meliloti about regulators of CtrA and FtsZ, as well as the processes that control bacteroid development. Here, we combine cell biology, biochemistry and bacterial genetics approaches to understand the function(s) of FcrX, a new factor that controls both CtrA and FtsZ, in free-living growth and in symbiosis. Depletion of the essential gene fcrX led to abnormally high levels of FtsZ and CtrA and minicell formation. Using multiple complementary techniques, we showed that FcrX is able to interact physically with FtsZ and CtrA. Moreover, its transcription is controlled by CtrA itself and displays an oscillatory pattern in the cell cycle. We further showed that, despite a weak homology with FliJ-like proteins, only FcrX proteins from closely-related species are able to complement S. meliloti fcrX function. Finally, deregulation of FcrX showed abnormal symbiotic behaviors in plants suggesting a putative role of this factor during bacteroid differentiation. In conclusion, FcrX is the first known cell cycle regulator that acts directly on both, CtrA and FtsZ, thereby controlling cell cycle, division and symbiotic differentiation.

microbiology↗

Sinorhizobium meliloti functions required for resistance to antimicrobial NCR peptides and bacteroid differentiation

Legumes of the Medicago genus form symbiosis with the bacterium Sinorhizobium meliloti and develop root nodules housing large numbers of the intracellular symbionts. Members of the Nodule-specific Cysteine Rich peptide (NCRs) family induce the endosymbionts into a terminal differentiated state. Individual cationic NCRs are antimicrobial peptides that have the capacity to kill the symbiont but the nodule cell environment prevents killing. Moreover, the bacterial broad-specificity peptide uptake transporter BacA and exopolysaccharides contribute to protect the endosymbionts against the toxic activity of NCRs. Here, we show that other S. meliloti functions participate in the protection of the endosymbionts, including an additional broad-specificity peptide uptake transporter encoded by the yejABEF genes, lipopolysaccharide modifications mediated by lpsB and lpxXL as well as rpoH1, encoding a stress sigma factor. Mutants of these genes show in vitro a strain-specific increased sensitivity profile against a panel of NCRs and form nodules in which bacteroid differentiation is affected. The lpsB mutant nodule bacteria do not differentiate, the lpxXL and rpoH1 mutants form some seemingly fully differentiated bacteroids although most of the nodule bacteria are undifferentiated, while the yejABEF mutants form hypertrophied but nitrogen-fixing bacteroids. The nodule bacteria of all the mutants have a strongly enhanced membrane permeability, which is dependent on the transport of NCRs to the endosymbionts. Our results suggest that S. meliloti relies on a suite of functions including peptide transporters, the bacterial envelope structures and stress response regulators to resist the aggressive assault of NCR peptides in the nodule cells. ImportanceThe nitrogen fixing symbiosis of legumes with rhizobium bacteria has a predominant ecological role in the nitrogen cycle and has the potential to provide the nitrogen required for plant growth in agriculture. The host plants allow the rhizobia to colonize specific symbiotic organs, the nodules, in large numbers in order to produce sufficient reduced nitrogen for the plant needs. Some legumes, including Medicago spp., produce massively antimicrobial peptides to keep this large bacterial population in check. These peptides, known as NCRs, have the potential to kill the rhizobia but in nodules, they rather inhibit the division of the bacteria, which maintain a high nitrogen fixing activity. In this study, we show that the tempering of the antimicrobial activity of the NCR peptides in the Medicago symbiont Sinorhizobium meliloti is multifactorial and requires the YejABEF peptide transporter, the lipopolysaccharide outer membrane composition and the stress response regulator RpoH1.

microbiology↗

Bradyrhizobium diazoefficiens USDA110 nodulation of Aeschynomene afraspera is associated with atypical terminal bacteroid differentiation and suboptimal symbiotic efficiency

Legume plants can form root organs called nodules where they house intracellular symbiotic rhizobium bacteria. Within nodule cells, rhizobia differentiate into bacteroids, which fix nitrogen for the benefit of the plant. Depending on the combination of host plants and rhizobial strains, the output of rhizobium-legume interactions is varying from non-fixing associations to symbioses that are highly beneficial for the plant. Bradyrhizobium diazoefficiens USDA110 was isolated as a soybean symbiont but it can also establish a functional symbiotic interaction with Aeschynomene afraspera. In contrast to soybean, A. afraspera triggers terminal bacteroid differentiation, a process involving bacterial cell elongation, polyploidy and membrane permeability leading to loss of bacterial viability while plants increase their symbiotic benefit. A combination of plant metabolomics, bacterial proteomics and transcriptomics along with cytological analyses was used to study the physiology of USDA110 bacteroids in these two host plants. We show that USDA110 establish a poorly efficient symbiosis with A. afraspera, despite the full activation of the bacterial symbiotic program. We found molecular signatures of high level of stress in A. afraspera bacteroids whereas those of terminal bacteroid differentiation were only partially activated. Finally, we show that in A. afraspera, USDA110 bacteroids undergo an atypical terminal differentiation hallmarked by the disconnection of the canonical features of this process. This study pinpoints how a rhizobium strain can adapt its physiology to a new host and cope with terminal differentiation when it did not co-evolve with such a host. ImportanceLegume-rhizobium symbiosis is a major ecological process in the nitrogen cycle, responsible for the main input of fixed nitrogen in the biosphere. The efficiency of this symbiosis relies on the coevolution of the partners. Some legume plants, but not all, optimize their return-on-investment in the symbiosis by imposing on their microsymbionts a terminal differentiation program that increases their symbiotic efficiency but imposes a high level of stress and drastically reduce their viability. We combined multi-omics with physiological analyses to show that the non-natural symbiotic couple formed by Bradyrhizobium diazoefficiens USDA110 and Aeschynomene afraspera is functional but displays a low symbiotic efficiency associated to a disconnection of terminal bacteroid differentiation features.

microbiology↗

ORP5 REGULATES TRANSPORT OF LIPIDS AND CALCIUM TO MITOCHONDRIA AT ENDOPLASMIC RETICULUM-MITOCHONDRIA MEMBRANE CONTACT SITES

Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membranes (MAMs) subdomains, physically linked to the MIB/MICOS complexes that bridge the two mitochondrial membranes. We also show that ORP5/8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a novel physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membranes contacts maintained by the MIB/MICOS complexes.

cell biology↗