VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins
The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC...
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| description | The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as 'non-toxic'. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of 'non-toxic' VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617--VapC proteins with similarity to Rv0549c and Rv3320c, respectively--these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism. |
| doi_str_mv | 10.1371/journal.pone.0021738 |
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The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as 'non-toxic'. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of 'non-toxic' VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617--VapC proteins with similarity to Rv0549c and Rv3320c, respectively--these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021738</identifier><identifier>PMID: 21738782</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Antitoxins ; Antitoxins - genetics ; Antitoxins - metabolism ; Artificial chromosomes ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Biological products ; Biology ; Chromosomes ; Councils ; Deletion mutant ; E coli ; Gene deletion ; Gene Expression Regulation, Bacterial - genetics ; Gene Expression Regulation, Bacterial - physiology ; Genes ; Genetic aspects ; Genomes ; Genomics ; Gram-negative bacteria ; Growth ; Health sciences ; Infectious diseases ; Laboratories ; Medical research ; Medicine ; Modules ; Mutation ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - growth & development ; Mycobacterium tuberculosis - metabolism ; Oxidative stress ; Physiology ; Proteins ; Ribonuclease ; Ribonucleases - genetics ; Ribonucleases - metabolism ; Ribonucleotide reductase ; Toxicity ; Toxins ; Tuberculosis ; Virulence-associated protein C ; Yeast</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e21738</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Ahidjo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as 'non-toxic'. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of 'non-toxic' VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617--VapC proteins with similarity to Rv0549c and Rv3320c, respectively--these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism.</description><subject>Analysis</subject><subject>Antitoxins</subject><subject>Antitoxins - genetics</subject><subject>Antitoxins - metabolism</subject><subject>Artificial chromosomes</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Biological products</subject><subject>Biology</subject><subject>Chromosomes</subject><subject>Councils</subject><subject>Deletion mutant</subject><subject>E coli</subject><subject>Gene deletion</subject><subject>Gene Expression Regulation, Bacterial - genetics</subject><subject>Gene Expression Regulation, Bacterial - physiology</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Gram-negative bacteria</subject><subject>Growth</subject><subject>Health sciences</subject><subject>Infectious diseases</subject><subject>Laboratories</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Modules</subject><subject>Mutation</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Mycobacterium tuberculosis - growth & development</subject><subject>Mycobacterium tuberculosis - metabolism</subject><subject>Oxidative stress</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Ribonuclease</subject><subject>Ribonucleases - genetics</subject><subject>Ribonucleases - metabolism</subject><subject>Ribonucleotide reductase</subject><subject>Toxicity</subject><subject>Toxins</subject><subject>Tuberculosis</subject><subject>Virulence-associated protein C</subject><subject>Yeast</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7jr6D0QDguDFjEnTNu2NsA5-DKws-LG3IU1O2yxtMiap7vgn_MtmZ7rLFBSkFy3J877n5G1OkjwleEUoI6-v7OiM6Fdba2CFcUoYLe8lp6Si6bJIMb1_9H2SPPL-CuOclkXxMDnZw6xMT5Pfl2K7RsFea-NR4-yAPu2krYUM4PQ4oDDW4OTYW689Eg6Q07U1o-xBePAodCIgpZsGHJigRd_vkDadrnVArbM_Q4eEUXuhgTE40etfoFC9Q9K2RgRAsf7byAR96OFx8qARvYcn03uRfHv_7uv64_L84sNmfXa-lEVFwrICVbKiyDNWgRB50ZSQS0oxMFk3MpVC0YqWOM9BVVLlDYOqqjDJFcGsriWhi-T5wXcbj8anLD0nlFRphrM8jcTmQCgrrvjW6UG4HbdC8_2CdS0XLuiYBMdVDlAqjGkOmWgywahgTcYoZCpTdRG93kzVxnoAJWNWMYqZ6XzH6I639genJC3KaLRIXkwGzn4fwYd_tDxRrYhdadPYaCYH7SU_y1hRxp_PcKRWf6Hio2DQMt6mRsf1meDVTBCZANehFaP3fPPl8_-zF5dz9uUR24HoQ-dtPwZtjZ-D2QGUznrvoLlLjmB-Mwy3afCbYeDTMETZs-PU70S3t5_-ARj-COw</recordid><startdate>20110629</startdate><enddate>20110629</enddate><creator>Ahidjo, Bintou Ahmadou</creator><creator>Kuhnert, Diane</creator><creator>McKenzie, Joanna L</creator><creator>Machowski, Edith E</creator><creator>Gordhan, Bhavna G</creator><creator>Arcus, Vickery</creator><creator>Abrahams, Garth L</creator><creator>Mizrahi, Valerie</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110629</creationdate><title>VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins</title><author>Ahidjo, Bintou Ahmadou ; Kuhnert, Diane ; McKenzie, Joanna L ; Machowski, Edith E ; Gordhan, Bhavna G ; Arcus, Vickery ; Abrahams, Garth L ; Mizrahi, Valerie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-9ed87665479eaa56f8e5c330e7cbfc2cad3938055ed9cd5f7e999015d107bbc13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis</topic><topic>Antitoxins</topic><topic>Antitoxins - 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The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as 'non-toxic'. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of 'non-toxic' VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617--VapC proteins with similarity to Rv0549c and Rv3320c, respectively--these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21738782</pmid><doi>10.1371/journal.pone.0021738</doi><tpages>e21738</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1319240452 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analysis Antitoxins Antitoxins - genetics Antitoxins - metabolism Artificial chromosomes Bacterial Proteins - genetics Bacterial Proteins - metabolism Biological products Biology Chromosomes Councils Deletion mutant E coli Gene deletion Gene Expression Regulation, Bacterial - genetics Gene Expression Regulation, Bacterial - physiology Genes Genetic aspects Genomes Genomics Gram-negative bacteria Growth Health sciences Infectious diseases Laboratories Medical research Medicine Modules Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - growth & development Mycobacterium tuberculosis - metabolism Oxidative stress Physiology Proteins Ribonuclease Ribonucleases - genetics Ribonucleases - metabolism Ribonucleotide reductase Toxicity Toxins Tuberculosis Virulence-associated protein C Yeast |
| title | VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T14%3A01%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=VapC%20toxins%20from%20Mycobacterium%20tuberculosis%20are%20ribonucleases%20that%20differentially%20inhibit%20growth%20and%20are%20neutralized%20by%20cognate%20VapB%20antitoxins&rft.jtitle=PloS%20one&rft.au=Ahidjo,%20Bintou%20Ahmadou&rft.date=2011-06-29&rft.volume=6&rft.issue=6&rft.spage=e21738&rft.pages=e21738-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0021738&rft_dat=%3Cgale_plos_%3EA476886670%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1319240452&rft_id=info:pmid/21738782&rft_galeid=A476886670&rft_doaj_id=oai_doaj_org_article_095ee8d0035e4af4a73a7f473e4d4db6&rfr_iscdi=true |