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Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole
The human pathogen Coxiella burnetii encodes a type IV secretion system called Dot/Icm that is essential for intracellular replication. The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have...
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Published in: | PloS one 2013-01, Vol.8 (1), p.e54566-e54566 |
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description | The human pathogen Coxiella burnetii encodes a type IV secretion system called Dot/Icm that is essential for intracellular replication. The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a β-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. Silencing of the host genes encoding the membrane transport regulators Rab5 or Rab7 interfered with effector translocation, which indicates that effectors are not translocated until bacteria traffic to a late endocytic compartment in the host cell. Similar requirements for effector translocation were discerned in bone marrow macrophages derived from C57BL/6 mice, which are primary cells that restrict the intracellular replication of C. burnetii. In addition to requiring endocytic maturation of the vacuole for Dot/Icm-mediated translocation of effectors, bacterial transcription was required for this process. Thus, translocation of effector proteins by the C. burnetii Dot/Icm system occurs after acidification of the CCV and maturation of this specialized organelle to a late endocytic compartment. This indicates that creation of the specialized vacuole in which C. burnetii replicates represents a two-stage process mediated initially by host factors that regulate endocytic maturation and then by bacterial effectors delivered into host cells after bacteria establish residency in a lysosome-derived organelle. |
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The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a β-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. Silencing of the host genes encoding the membrane transport regulators Rab5 or Rab7 interfered with effector translocation, which indicates that effectors are not translocated until bacteria traffic to a late endocytic compartment in the host cell. Similar requirements for effector translocation were discerned in bone marrow macrophages derived from C57BL/6 mice, which are primary cells that restrict the intracellular replication of C. burnetii. In addition to requiring endocytic maturation of the vacuole for Dot/Icm-mediated translocation of effectors, bacterial transcription was required for this process. Thus, translocation of effector proteins by the C. burnetii Dot/Icm system occurs after acidification of the CCV and maturation of this specialized organelle to a late endocytic compartment. This indicates that creation of the specialized vacuole in which C. burnetii replicates represents a two-stage process mediated initially by host factors that regulate endocytic maturation and then by bacterial effectors delivered into host cells after bacteria establish residency in a lysosome-derived organelle.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0054566</identifier><identifier>PMID: 23349930</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acidification ; Animals ; Apoptosis ; Bacteria ; Bacterial Secretion Systems - genetics ; Beta lactamases ; beta-Lactamases - genetics ; beta-Lactamases - metabolism ; Biology ; Bone marrow ; Carrier Proteins - metabolism ; Coxiella burnetii ; Coxiella burnetii - genetics ; Coxiella burnetii - metabolism ; Coxiella burnetii - pathogenicity ; Cytosol ; Effectors ; Extracellular Matrix - metabolism ; Genetic engineering ; Health aspects ; HeLa Cells ; Host-Pathogen Interactions - genetics ; Humans ; Infection ; Infections ; Intracellular ; Legionella ; Macrophages ; Maturation ; Medical research ; Membrane Transport Proteins - genetics ; Membrane Transport Proteins - metabolism ; Metabolism ; Mice ; Mice, Inbred C57BL ; Morphology ; Pathogenesis ; Pathogens ; Protein transport ; Protein Transport - genetics ; Proteins ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Regulators ; Replication ; Secretion ; Transcription ; Translocation ; Vacuoles - metabolism ; Vacuoles - microbiology</subject><ispartof>PloS one, 2013-01, Vol.8 (1), p.e54566-e54566</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Newton 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. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Newton et al 2013 Newton et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-97e1672f74612a8d9bfc40e3a6efdd61b437dc332182838c8ca281fda09a8c053</citedby><cites>FETCH-LOGICAL-c758t-97e1672f74612a8d9bfc40e3a6efdd61b437dc332182838c8ca281fda09a8c053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1327279431/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1327279431?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23349930$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kwaik, Yousef Abu</contributor><creatorcontrib>Newton, Hayley J</creatorcontrib><creatorcontrib>McDonough, Justin A</creatorcontrib><creatorcontrib>Roy, Craig R</creatorcontrib><title>Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The human pathogen Coxiella burnetii encodes a type IV secretion system called Dot/Icm that is essential for intracellular replication. The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a β-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. 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genetics</subject><subject>Humans</subject><subject>Infection</subject><subject>Infections</subject><subject>Intracellular</subject><subject>Legionella</subject><subject>Macrophages</subject><subject>Maturation</subject><subject>Medical research</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Membrane Transport Proteins - metabolism</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Morphology</subject><subject>Pathogenesis</subject><subject>Pathogens</subject><subject>Protein transport</subject><subject>Protein Transport - genetics</subject><subject>Proteins</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Regulators</subject><subject>Replication</subject><subject>Secretion</subject><subject>Transcription</subject><subject>Translocation</subject><subject>Vacuoles - metabolism</subject><subject>Vacuoles - microbiology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8tq3DAUhk1padK0b1BaQaG0i5lYl7HkTSBM03YgEOglWyHLRzMKtuVIcsg8SV-3mkvCuGRRvLCRv_8_Or90suwtzqeYcnx64wbfqWbauw6meT5js6J4lh3jkpJJQXL6_OD7KHsVwk2CqCiKl9kRoZSVJc2Psz8XxoCOzqPeuwi2Q9GrLjROq2hdh6o1iitAc3dvoWkUqlJRiNaiLy6eLnSL4roHtLhGAbSHrSSsQ4QWebgdrIeAoKudXkerUavi4He-zmx9exVXbgndxGk99BZqdKf04Bp4nb0wqgnwZv8-yX5_vfg1_z65vPq2mJ9fTjSfiTgpOeCCE8NZgYkSdVkZzXKgqgBT1wWuGOW1ppRgQQQVWmhFBDa1yksldMrjJHu_8-0bF-Q-0yAxJZzwklGciMWOqJ26kb23rfJr6ZSV2wXnl1L51F0DknFDmM4xNzPBmCorqnClKa8qTsuak-R1tq82VC3UGrqUdjMyHf_p7Eou3Z2kM8aFyJPBp72Bd7cDhChbG_TmZDpwQ9o3ESRnKRKR0A__oE93t6eWKjVgO-NSXb0xleepJGGkzFmipk9Q6amhtTpdQGPT-kjweSRITIT7uFRDCHLx88f_s1fXY_bjAbsC1cRVcM2wuVNhDLIdqL0LwYN5DBnncjM_D2nIzfzI_fwk2bvDA3oUPQwM_Qs7CBhH</recordid><startdate>20130117</startdate><enddate>20130117</enddate><creator>Newton, Hayley J</creator><creator>McDonough, Justin A</creator><creator>Roy, Craig R</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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130117</creationdate><title>Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole</title><author>Newton, Hayley J ; McDonough, Justin A ; Roy, Craig R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-97e1672f74612a8d9bfc40e3a6efdd61b437dc332182838c8ca281fda09a8c053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acidification</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bacteria</topic><topic>Bacterial Secretion Systems - 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The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a β-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. Silencing of the host genes encoding the membrane transport regulators Rab5 or Rab7 interfered with effector translocation, which indicates that effectors are not translocated until bacteria traffic to a late endocytic compartment in the host cell. Similar requirements for effector translocation were discerned in bone marrow macrophages derived from C57BL/6 mice, which are primary cells that restrict the intracellular replication of C. burnetii. In addition to requiring endocytic maturation of the vacuole for Dot/Icm-mediated translocation of effectors, bacterial transcription was required for this process. Thus, translocation of effector proteins by the C. burnetii Dot/Icm system occurs after acidification of the CCV and maturation of this specialized organelle to a late endocytic compartment. This indicates that creation of the specialized vacuole in which C. burnetii replicates represents a two-stage process mediated initially by host factors that regulate endocytic maturation and then by bacterial effectors delivered into host cells after bacteria establish residency in a lysosome-derived organelle.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23349930</pmid><doi>10.1371/journal.pone.0054566</doi><tpages>e54566</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acidification Animals Apoptosis Bacteria Bacterial Secretion Systems - genetics Beta lactamases beta-Lactamases - genetics beta-Lactamases - metabolism Biology Bone marrow Carrier Proteins - metabolism Coxiella burnetii Coxiella burnetii - genetics Coxiella burnetii - metabolism Coxiella burnetii - pathogenicity Cytosol Effectors Extracellular Matrix - metabolism Genetic engineering Health aspects HeLa Cells Host-Pathogen Interactions - genetics Humans Infection Infections Intracellular Legionella Macrophages Maturation Medical research Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Metabolism Mice Mice, Inbred C57BL Morphology Pathogenesis Pathogens Protein transport Protein Transport - genetics Proteins Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Regulators Replication Secretion Transcription Translocation Vacuoles - metabolism Vacuoles - microbiology |
title | Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole |
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