The PhoP-Dependent ncRNA Mcr7 Modulates the TAT Secretion System in Mycobacterium tuberculosis
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{"title"=>"The PhoP-Dependent ncRNA Mcr7 Modulates the TAT Secretion System in Mycobacterium tuberculosis", "type"=>"journal", "authors"=>[{"first_name"=>"Luis", "last_name"=>"Solans", "scopus_author_id"=>"56185579100"}, {"first_name"=>"Jesús", "last_name"=>"Gonzalo-Asensio", "scopus_author_id"=>"12783547500"}, {"first_name"=>"Claudia", "last_name"=>"Sala", "scopus_author_id"=>"8160947600"}, {"first_name"=>"Andrej", "last_name"=>"Benjak", "scopus_author_id"=>"24921398500"}, {"first_name"=>"Swapna", "last_name"=>"Uplekar", "scopus_author_id"=>"26535177700"}, {"first_name"=>"Jacques", "last_name"=>"Rougemont", "scopus_author_id"=>"6603112050"}, {"first_name"=>"Christophe", "last_name"=>"Guilhot", "scopus_author_id"=>"6701631806"}, {"first_name"=>"Wladimir", "last_name"=>"Malaga", "scopus_author_id"=>"6506169311"}, {"first_name"=>"Carlos", "last_name"=>"Martín", "scopus_author_id"=>"7405842809"}, {"first_name"=>"Stewart T.", "last_name"=>"Cole", "scopus_author_id"=>"7401503569"}], "year"=>2014, "source"=>"PLoS Pathogens", "identifiers"=>{"pui"=>"373203746", "sgr"=>"84901687221", "issn"=>"15537374", "pmid"=>"24874799", "scopus"=>"2-s2.0-84901687221", "doi"=>"10.1371/journal.ppat.1004183", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)"}, "id"=>"788a27cb-d3ba-3597-b15f-2869fa8a8cb0", "abstract"=>"The PhoPR two-component system is essential for virulence in Mycobacterium tuberculosis where it controls expression of approximately 2% of the genes, including those for the ESX-1 secretion apparatus, a major virulence determinant. Mutations in phoP lead to compromised production of pathogen-specific cell wall components and attenuation both ex vivo and in vivo. Using antibodies against the native protein in ChIP-seq experiments (chromatin immunoprecipitation followed by high-throughput sequencing) we demonstrated that PhoP binds to at least 35 loci on the M. tuberculosis genome. The PhoP regulon comprises several transcriptional regulators as well as genes for polyketide synthases and PE/PPE proteins. Integration of ChIP-seq results with high-resolution transcriptomic analysis (RNA-seq) revealed that PhoP controls 30 genes directly, whilst regulatory cascades are responsible for signal amplification and downstream effects through proteins like EspR, which controls Esx1 function, via regulation of the espACD operon. The most prominent site of PhoP regulation was located in the intergenic region between rv2395 and PE_PGRS41, where the mcr7 gene codes for a small non-coding RNA (ncRNA). Northern blot experiments confirmed the absence of Mcr7 in an M. tuberculosis phoP mutant as well as low-level expression of the ncRNA in M. tuberculosis complex members other than M. tuberculosis. By means of genetic and proteomic analyses we demonstrated that Mcr7 modulates translation of the tatC mRNA thereby impacting the activity of the Twin Arginine Translocation (Tat) protein secretion apparatus. As a result, secretion of the immunodominant Ag85 complex and the beta-lactamase BlaC is affected, among others. Mcr7, the first ncRNA of M. tuberculosis whose function has been established, therefore represents a missing link between the PhoPR two-component system and the downstream functions necessary for successful infection of the host.", "link"=>"http://www.mendeley.com/research/phopdependent-ncrna-mcr7-modulates-tat-secretion-system-mycobacterium-tuberculosis", "reader_count"=>84, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>9, "Researcher"=>17, "Student > Ph. D. Student"=>29, "Student > Postgraduate"=>5, "Student > Master"=>15, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>9, "Researcher"=>17, "Student > Ph. D. Student"=>29, "Student > Postgraduate"=>5, "Student > Master"=>15, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Unspecified"=>4, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>21, "Agricultural and Biological Sciences"=>42, "Medicine and Dentistry"=>6, "Veterinary Science and Veterinary Medicine"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>42}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>21}, "Unspecified"=>{"Unspecified"=>4}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>2}}, "reader_count_by_country"=>{"Colombia"=>1, "South Africa"=>1, "Israel"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1513551"], "description"=>"<p><b>A.</b> Heat map displaying values from in-depth proteomic quantifications of the secreted protein fraction. Values for EsxA, EsxB, EspA and EspC are displayed as internal controls since these proteins are barely detectable in the <i>M. tuberculosis phoP</i> mutant. The other proteins are representative examples of putative Tat-secreted substrates according to <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-SaintJoanis1\" target=\"_blank\">[24]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-Marrichi1\" target=\"_blank\">[26]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-Dilks1\" target=\"_blank\">[27]</a>. Note the opposite trend between EsxA/EsxB/EspA/EspC and Tat-secreted proteins. <b>B.</b> Western blot analysis of Ag85C, Rv2525c and EsxA in <i>M. tuberculosis</i> wild type, <i>phoP</i> mutant and complemented strains. Results are representative of three independent experiments. <b>C.</b> Proposed regulatory network involving PhoP, Mcr7 and <i>tatC</i>. PhoP controls transcription of Mcr7 (red transcript), which anneals to the 5′-end of the <i>tatC</i> mRNA (blue transcript) occluding the RBS (boxed) and consequently impairing translation of TatC. <b>D.</b> Northern blot analysis of Mcr7 in wild type, <i>phoP</i> mutant and <i>mcr7</i>-complemented strains of <i>M. tuberculosis</i>. Introduction of <i>mcr7</i> under the 16S rRNA promoter in a <i>phoP</i> mutant efficiently restores production of this molecule. Expression of the 5S rRNA is used as a control of RNA loaded in each lane. <b>E.</b> Analysis of TatC expression by Western blot in wild type, <i>phoP</i> mutant, <i>phoP</i>-complemented mutant and <i>mcr7</i>-complemented strains of <i>M. tuberculosis</i>. Note the higher expression levels of TatC in the <i>phoP</i> mutant compared to the wild type. Complementation of a <i>phoP</i> mutant with <i>phoP</i> or <i>mcr7</i> restored wild type levels of TatC. GroEL2 is used as a control of protein loaded in each lane. Signal intensity was quantified from three independent experiments and plotted in the graphs below the Western blot images.</p>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "secretome", "identifies", "tat", "substrates", "enriched", "tuberculosis"], "article_id"=>1039893, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004183.g003", "stats"=>{"downloads"=>1, "page_views"=>37, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_the_M_tuberculosis_secretome_identifies_a_high_proportion_of_Tat_substrates_enriched_in_the_M_tuberculosis_phoP_mutant_/1039893", "title"=>"Analysis of the <i>M. tuberculosis</i> secretome identifies a high proportion of Tat substrates enriched in the <i>M. tuberculosis phoP</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-29 03:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1513550"], "description"=>"<p><b>A.</b> Diagram showing chromosomal location of <i>mcr7</i> in the <i>rv2395</i>-<i>PE</i>_<i>PGRS41</i> intergenic region. ChIP-seq and RNA-seq profiles of the <i>mcr7</i> locus showing PhoP binding and transcriptional signals. Note the absence of transcription in the <i>phoP</i> mutant that correlates with lack of PhoP-binding in this strain. <b>B.</b> Northern blot analysis using a <i>mcr7</i> antisense probe in wild type, <i>phoP</i> mutant and <i>phoP</i>-complemented strains in H37Rv and Beijing GC1237 genetic backgrounds. Detection of the Mcr7 transcript in the primary, unprocessed transcriptome from H37Rv is also shown. Expression of the 5S rRNA is used as a control of RNA loaded in each lane. <b>C.</b> Northern blot analysis of Mcr7 in representative species of the <i>M. tuberculosis</i> complex. Note the higher expression level of this non-coding RNA in <i>M. tuberculosis</i> H37Rv relative to other members of the <i>M. tuberculosis</i> complex. Expression of the 5S rRNA is used as a control of RNA loaded in each lane. <b>D.</b> Complementarity between Mcr7 and the 5′-end of the <i>tatC</i> mRNA. The predicted ribosome binding site (RBS) and positions of the first 6 codons of <i>tatC</i> are indicated. <b>E.</b> Schematic representation of the Tat system involved in protein translocation from the cytoplasm to the extracellular environment. TatC is involved in recognition of Arg-Arg (RR) motifs within the signal peptide of secreted proteins.</p>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "phop-regulated"], "article_id"=>1039892, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004183.g002", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_mcr7_as_the_major_PhoP_regulated_target_/1039892", "title"=>"Characterization of <i>mcr7</i> as the major PhoP-regulated target.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-29 03:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1513553"], "description"=>"<p>The table lists regions enriched in immunoprecipitated PhoP-DNA complexes from the H37Rv wild type strain as compared to the <i>phoP</i> mutant. Fold change expression values as determined by RNA-seq experiments are also reported for the flanking genes. Predicted or validated operons found to be deregulated in the <i>phoP</i> mutant are indicated.</p>a<p>p value <0.0001.</p>b<p>FDR 0.00%.</p>c<p>This column lists the predicted operons (according to <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-Uplekar1\" target=\"_blank\">[17]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-Roback1\" target=\"_blank\">[18]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004183#ppat.1004183-Price1\" target=\"_blank\">[19]</a>), located downstream of PhoP binding sites, that were found to be deregulated in the <i>phoP</i> mutant compared to the wild type strain.</p>§<p>Region detected is between two genes transcribed in opposite direction.</p>£<p>Region located in 3′-end of the gene.</p><p>ND: fold change expression levels of <i>phoP</i> were not quantified since the gene carries a deletion in the mutant strain.</p>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "ChIP-seq", "localization", "phop", "binding", "sites"], "article_id"=>1039895, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004183.t001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_ChIP_seq_results_showing_localization_of_PhoP_binding_sites_in_the_M_tuberculosis_genome_/1039895", "title"=>"Summary of ChIP-seq results showing localization of PhoP binding sites in the <i>M. tuberculosis</i> genome.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-29 03:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1513554", "https://ndownloader.figshare.com/files/1513555", "https://ndownloader.figshare.com/files/1513556", "https://ndownloader.figshare.com/files/1513557", "https://ndownloader.figshare.com/files/1513558", "https://ndownloader.figshare.com/files/1513559", "https://ndownloader.figshare.com/files/1513560", "https://ndownloader.figshare.com/files/1513561", "https://ndownloader.figshare.com/files/1513562", "https://ndownloader.figshare.com/files/1513563"], "description"=>"<div><p>The PhoPR two-component system is essential for virulence in <i>Mycobacterium tuberculosis</i> where it controls expression of approximately 2% of the genes, including those for the ESX-1 secretion apparatus, a major virulence determinant. Mutations in <i>phoP</i> lead to compromised production of pathogen-specific cell wall components and attenuation both <i>ex vivo</i> and <i>in vivo</i>. Using antibodies against the native protein in ChIP-seq experiments (chromatin immunoprecipitation followed by high-throughput sequencing) we demonstrated that PhoP binds to at least 35 loci on the <i>M. tuberculosis</i> genome. The PhoP regulon comprises several transcriptional regulators as well as genes for polyketide synthases and PE/PPE proteins. Integration of ChIP-seq results with high-resolution transcriptomic analysis (RNA-seq) revealed that PhoP controls 30 genes directly, whilst regulatory cascades are responsible for signal amplification and downstream effects through proteins like EspR, which controls Esx1 function, <i>via</i> regulation of the <i>espACD</i> operon. The most prominent site of PhoP regulation was located in the intergenic region between <i>rv2395</i> and <i>PE_PGRS41</i>, where the <i>mcr7</i> gene codes for a small non-coding RNA (ncRNA). Northern blot experiments confirmed the absence of Mcr7 in an <i>M. tuberculosis phoP</i> mutant as well as low-level expression of the ncRNA in <i>M. tuberculosis</i> complex members other than <i>M. tuberculosis</i>. By means of genetic and proteomic analyses we demonstrated that Mcr7 modulates translation of the <i>tatC</i> mRNA thereby impacting the activity of the Twin Arginine Translocation (Tat) protein secretion apparatus. As a result, secretion of the immunodominant Ag85 complex and the beta-lactamase BlaC is affected, among others. Mcr7, the first ncRNA of <i>M. tuberculosis</i> whose function has been established, therefore represents a missing link between the PhoPR two-component system and the downstream functions necessary for successful infection of the host.</p></div>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "phop-dependent", "ncrna", "mcr7", "modulates", "tat", "secretion"], "article_id"=>1039896, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1004183.s001", "https://dx.doi.org/10.1371/journal.ppat.1004183.s002", "https://dx.doi.org/10.1371/journal.ppat.1004183.s003", "https://dx.doi.org/10.1371/journal.ppat.1004183.s004", "https://dx.doi.org/10.1371/journal.ppat.1004183.s005", "https://dx.doi.org/10.1371/journal.ppat.1004183.s006", "https://dx.doi.org/10.1371/journal.ppat.1004183.s007", "https://dx.doi.org/10.1371/journal.ppat.1004183.s008", "https://dx.doi.org/10.1371/journal.ppat.1004183.s009", "https://dx.doi.org/10.1371/journal.ppat.1004183.s010"], "stats"=>{"downloads"=>35, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_PhoP_Dependent_ncRNA_Mcr7_Modulates_the_TAT_Secretion_System_in_Mycobacterium_tuberculosis_/1039896", "title"=>"The PhoP-Dependent ncRNA Mcr7 Modulates the TAT Secretion System in <i>Mycobacterium tuberculosis</i>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-05-29 03:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1513552"], "description"=>"<p><b>A.</b> qRT-PCR analysis of <i>tatC</i>, <i>mcr7</i> and other genes from the PhoP regulon (<i>lipF</i>, <i>pks2</i>, <i>pks3</i>, <i>narK1</i> and <i>fadD21</i>). Bars represent fold changes in the expression levels in the <i>phoP</i> mutant and <i>mcr7</i>-complemented strains relative to <i>M. tuberculosis</i> wild type grown exponentially in 7H9 medium. Expression of the <i>tatC</i> mRNA is independent of <i>phoP</i> mutation and <i>mcr7</i> expression. Note that complementation with <i>mcr7</i> does not affect expression of the PhoP regulon. Results are representative of three independent experiments and error bars are the standard deviation of the mean. <b>B.</b> Western blot experiments of GroEL2, Ag85C, EspD and EsxA in the whole cell and secreted fractions of <i>M. tuberculosis</i> wild type, its <i>phoP</i> mutant and the <i>mcr7</i>-complemented strains. Equal protein amounts were loaded per well. GroEL2 is used as a control of bacterial integrity in each sample. Signal intensity was quantified and plotted in the graphs below the Western blot images. Results are representative of three independent experiments. <b>C.</b> Measure of β-lactamase activity of the BlaC protein by nitrocefin chromogenic assay. Activity is calculated relative to the CFU/ml in each strain.</p>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "tuberculosis", "mutant", "restores", "secretion", "tat-dependent", "substrates"], "article_id"=>1039894, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004183.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reintroduction_of_mcr7_in_an_M_tuberculosis_phoP_mutant_restores_secretion_of_Tat_dependent_substrates_to_wild_type_levels_/1039894", "title"=>"Reintroduction of <i>mcr7</i> in an <i>M. tuberculosis phoP</i> mutant restores secretion of Tat-dependent substrates to wild type levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-29 03:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1513549"], "description"=>"<p><b>A.</b> UCSC genome browser view showing PhoP binding regions across the <i>M. tuberculosis</i> genome. Peak height correlates with sequence reads and consequently with PhoP binding affinity. The use of a <i>phoP</i> mutant in this experiment (bottom panel) allows identification of false positive signals. <b>B.</b> PhoP and RNA polymerase (RNApol) ChIP-seq profiles for selected genes. Note that the PhoP binding site lies upstream that of RNApol for <i>lipF</i>, <i>narK1</i>, <i>pks2</i> and <i>pks3</i>, known to be transcriptionally activated by PhoP. The position of the PhoP binding region lies downstream that of RNApol for the <i>PE8</i> gene. PhoP binding at the 3′-end of <i>hddA</i> is shown as an example of non-canonical target. <b>C.</b> Bar diagram showing distance (in bp) between the PhoP binding sites and the start codon of adjacent ORFs. <b>D.</b> Bar diagram showing distance between the position of the PhoP binding site and the summit of the RNApol peak calculated from ChIP-seq data. <b>E.</b> Sequence logo showing the consensus sequence derived from the PhoP binding sites identified by ChIP-seq.</p>", "links"=>[], "tags"=>["genetics", "genomics", "microbiology", "phop", "binding", "sites", "chromosome"], "article_id"=>1039891, "categories"=>["Biological Sciences"], "users"=>["Luis Solans", "Jesús Gonzalo-Asensio", "Claudia Sala", "Andrej Benjak", "Swapna Uplekar", "Jacques Rougemont", "Christophe Guilhot", "Wladimir Malaga", "Carlos Martin", "Stewart T. Cole"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004183.g001", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mapping_of_PhoP_binding_sites_in_the_M_tuberculosis_chromosome_by_ChIP_seq_/1039891", "title"=>"Mapping of PhoP binding sites in the <i>M. tuberculosis</i> chromosome by ChIP-seq.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-29 03:44:09"}

PMC Usage Stats | Further Information

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