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Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways
The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabili...
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Published in: | PLoS pathogens 2010-09, Vol.6 (9), p.e1001128-e1001128 |
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creator | Jubelin, Grégory Taieb, Frédéric Duda, David M Hsu, Yun Samba-Louaka, Ascel Nobe, Rika Penary, Marie Watrin, Claude Nougayrède, Jean-Philippe Schulman, Brenda A Stebbins, C Erec Oswald, Eric |
description | The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria. |
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Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1001128</identifier><identifier>PMID: 20941356</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actins - metabolism ; Animals ; Bacterial infections ; Bacterial proteins ; Bacteriology ; Blotting, Western ; Cell Behavior ; Cell Biology/Cell Growth and Division ; Cell Biology/Cell Signaling ; Cell Cycle ; Cell Nucleus - metabolism ; Cells, Cultured ; Cellular Biology ; cullin ; Cyclin-dependent kinase inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; Development and progression ; Ecology, environment ; Enzymes ; Escherichia coli - pathogenicity ; Escherichia coli Infections - metabolism ; Escherichia coli Infections - microbiology ; Escherichia coli Infections - pathology ; Escherichia coli Proteins - metabolism ; Health ; Health aspects ; Human health and pathology ; Humans ; Immunity ; Immunoprecipitation ; Infection ; Infectious diseases ; Infectious Diseases/Bacterial Infections ; Infectious Diseases/Gastrointestinal Infections ; Infectious Diseases/Tropical and Travel-Associated Diseases ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinases ; Life Sciences ; Microbiology and Parasitology ; Microbiology/Parasitology ; Molecular Biology ; NEDD8 Protein ; Nuclei ; Pathogenic microorganisms ; Pathogens ; Physiological aspects ; proteasomes ; Protein Transport ; Proteins ; Rats ; scaffolds ; Signal Transduction ; SKP Cullin F-Box Protein Ligases - metabolism ; Subcellular Processes ; Symbiosis ; Toxins ; Transcription ; Two-Hybrid System Techniques ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitination ; Ubiquitins - genetics ; Ubiquitins - metabolism ; virulence factors</subject><ispartof>PLoS pathogens, 2010-09, Vol.6 (9), p.e1001128-e1001128</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>Attribution</rights><rights>Jubelin et al. 2010</rights><rights>2010 Jubelin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Jubelin G, Taieb F, Duda DM, Hsu Y, Samba-Louaka A, et al. (2010) Pathogenic Bacteria Target NEDD8-Conjugated Cullins to Hijack Host-Cell Signaling Pathways. 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Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria.</description><subject>Actins - metabolism</subject><subject>Animals</subject><subject>Bacterial infections</subject><subject>Bacterial proteins</subject><subject>Bacteriology</subject><subject>Blotting, Western</subject><subject>Cell Behavior</subject><subject>Cell Biology/Cell Growth and Division</subject><subject>Cell Biology/Cell Signaling</subject><subject>Cell Cycle</subject><subject>Cell Nucleus - metabolism</subject><subject>Cells, Cultured</subject><subject>Cellular Biology</subject><subject>cullin</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Cyclin-Dependent Kinase Inhibitor p27</subject><subject>Development and progression</subject><subject>Ecology, environment</subject><subject>Enzymes</subject><subject>Escherichia coli - pathogenicity</subject><subject>Escherichia coli Infections - metabolism</subject><subject>Escherichia coli Infections - microbiology</subject><subject>Escherichia coli Infections - pathology</subject><subject>Escherichia coli Proteins - metabolism</subject><subject>Health</subject><subject>Health aspects</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunoprecipitation</subject><subject>Infection</subject><subject>Infectious diseases</subject><subject>Infectious Diseases/Bacterial Infections</subject><subject>Infectious Diseases/Gastrointestinal Infections</subject><subject>Infectious Diseases/Tropical and Travel-Associated Diseases</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Microbiology and Parasitology</subject><subject>Microbiology/Parasitology</subject><subject>Molecular Biology</subject><subject>NEDD8 Protein</subject><subject>Nuclei</subject><subject>Pathogenic microorganisms</subject><subject>Pathogens</subject><subject>Physiological aspects</subject><subject>proteasomes</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>Rats</subject><subject>scaffolds</subject><subject>Signal Transduction</subject><subject>SKP Cullin F-Box Protein Ligases - metabolism</subject><subject>Subcellular Processes</subject><subject>Symbiosis</subject><subject>Toxins</subject><subject>Transcription</subject><subject>Two-Hybrid System Techniques</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitination</subject><subject>Ubiquitins - genetics</subject><subject>Ubiquitins - metabolism</subject><subject>virulence factors</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqVk8tu1DAUhiMEoqXwBggisUBdZPA1sTeVRm2hI40K4rJhY9mOnXjIxEPs9PL2OMy06iAkhLywdfz952afLHsJwQziCr5b-XHoZTfbbGScQQAgROxRdggpxUWFK_L4wfkgexbCCgACMSyfZgcI8HSk5WH2_ZOMrW9M73SupI5mcDKPcmhMzC_Pz85YoX2_GhsZTZ3rsetcH_Lo89atpP6Rtz7EQpuuy4NrUjaub_KUT3stb8Pz7ImVXTAvdvtR9u39-dfTi2L58cPidL4sdFWSWCjKGC-JhJJpgxS31GCKDcZIVpxCbUrFqkpbS1lFpaWIs9rClD2tFbQK4aPs9dbvpvNB7NoSRGoHh4BBxhOx2BK1lyuxGdxaDrfCSyd-G_zQCDlEpzsjrNVAg6SkSJEaQUUk4AoYW1usVD1FO9lFG9Xa1Nr0cZDdntP9m961ovFXAnFScc6Sg-Otg_YP2cV8KSYbQDwVyfEVTOzbXbDB_xxNiGLtwtRu2Rs_BsFKTisKEP0nWVEGMeGEJPLNlmxkqtf11qc09USLOcI81U7w1LLZX6i0arN26UsY65J9T3C8J0hMNDexkWMIYvHl83-wl_ss2bJ68CEMxt73DAIxDcLdi4tpEMRuEJLs1cNnuhfd_Xz8C75rA_c</recordid><startdate>20100901</startdate><enddate>20100901</enddate><creator>Jubelin, Grégory</creator><creator>Taieb, Frédéric</creator><creator>Duda, David M</creator><creator>Hsu, Yun</creator><creator>Samba-Louaka, Ascel</creator><creator>Nobe, Rika</creator><creator>Penary, Marie</creator><creator>Watrin, Claude</creator><creator>Nougayrède, Jean-Philippe</creator><creator>Schulman, Brenda A</creator><creator>Stebbins, C Erec</creator><creator>Oswald, Eric</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>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>7QL</scope><scope>C1K</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9902-0663</orcidid><orcidid>https://orcid.org/0000-0001-9612-2069</orcidid><orcidid>https://orcid.org/0000-0002-6802-1890</orcidid><orcidid>https://orcid.org/0000-0003-4417-6254</orcidid></search><sort><creationdate>20100901</creationdate><title>Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways</title><author>Jubelin, Grégory ; Taieb, Frédéric ; Duda, David M ; Hsu, Yun ; Samba-Louaka, Ascel ; Nobe, Rika ; Penary, Marie ; Watrin, Claude ; Nougayrède, Jean-Philippe ; Schulman, Brenda A ; Stebbins, C Erec ; Oswald, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c764t-b588964a1a8ce2b9f5e353e332a7951ce6b877cff5875af5298df11355db1fb23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Actins - metabolism</topic><topic>Animals</topic><topic>Bacterial infections</topic><topic>Bacterial proteins</topic><topic>Bacteriology</topic><topic>Blotting, Western</topic><topic>Cell Behavior</topic><topic>Cell Biology/Cell Growth and Division</topic><topic>Cell Biology/Cell Signaling</topic><topic>Cell Cycle</topic><topic>Cell Nucleus - metabolism</topic><topic>Cells, Cultured</topic><topic>Cellular Biology</topic><topic>cullin</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p27</topic><topic>Development and progression</topic><topic>Ecology, environment</topic><topic>Enzymes</topic><topic>Escherichia coli - pathogenicity</topic><topic>Escherichia coli Infections - metabolism</topic><topic>Escherichia coli Infections - microbiology</topic><topic>Escherichia coli Infections - pathology</topic><topic>Escherichia coli Proteins - metabolism</topic><topic>Health</topic><topic>Health aspects</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Immunity</topic><topic>Immunoprecipitation</topic><topic>Infection</topic><topic>Infectious diseases</topic><topic>Infectious Diseases/Bacterial Infections</topic><topic>Infectious Diseases/Gastrointestinal Infections</topic><topic>Infectious Diseases/Tropical and Travel-Associated Diseases</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Microbiology and Parasitology</topic><topic>Microbiology/Parasitology</topic><topic>Molecular Biology</topic><topic>NEDD8 Protein</topic><topic>Nuclei</topic><topic>Pathogenic microorganisms</topic><topic>Pathogens</topic><topic>Physiological aspects</topic><topic>proteasomes</topic><topic>Protein Transport</topic><topic>Proteins</topic><topic>Rats</topic><topic>scaffolds</topic><topic>Signal Transduction</topic><topic>SKP Cullin F-Box Protein Ligases - metabolism</topic><topic>Subcellular Processes</topic><topic>Symbiosis</topic><topic>Toxins</topic><topic>Transcription</topic><topic>Two-Hybrid System Techniques</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitination</topic><topic>Ubiquitins - genetics</topic><topic>Ubiquitins - metabolism</topic><topic>virulence factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jubelin, Grégory</creatorcontrib><creatorcontrib>Taieb, Frédéric</creatorcontrib><creatorcontrib>Duda, David M</creatorcontrib><creatorcontrib>Hsu, Yun</creatorcontrib><creatorcontrib>Samba-Louaka, Ascel</creatorcontrib><creatorcontrib>Nobe, Rika</creatorcontrib><creatorcontrib>Penary, Marie</creatorcontrib><creatorcontrib>Watrin, Claude</creatorcontrib><creatorcontrib>Nougayrède, Jean-Philippe</creatorcontrib><creatorcontrib>Schulman, Brenda A</creatorcontrib><creatorcontrib>Stebbins, C Erec</creatorcontrib><creatorcontrib>Oswald, Eric</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jubelin, Grégory</au><au>Taieb, Frédéric</au><au>Duda, David M</au><au>Hsu, Yun</au><au>Samba-Louaka, Ascel</au><au>Nobe, Rika</au><au>Penary, Marie</au><au>Watrin, Claude</au><au>Nougayrède, Jean-Philippe</au><au>Schulman, Brenda A</au><au>Stebbins, C Erec</au><au>Oswald, Eric</au><au>Van Nhieu, Guy Tran</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2010-09-01</date><risdate>2010</risdate><volume>6</volume><issue>9</issue><spage>e1001128</spage><epage>e1001128</epage><pages>e1001128-e1001128</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. 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subjects | Actins - metabolism Animals Bacterial infections Bacterial proteins Bacteriology Blotting, Western Cell Behavior Cell Biology/Cell Growth and Division Cell Biology/Cell Signaling Cell Cycle Cell Nucleus - metabolism Cells, Cultured Cellular Biology cullin Cyclin-dependent kinase inhibitor p21 Cyclin-Dependent Kinase Inhibitor p21 - metabolism Cyclin-Dependent Kinase Inhibitor p27 Development and progression Ecology, environment Enzymes Escherichia coli - pathogenicity Escherichia coli Infections - metabolism Escherichia coli Infections - microbiology Escherichia coli Infections - pathology Escherichia coli Proteins - metabolism Health Health aspects Human health and pathology Humans Immunity Immunoprecipitation Infection Infectious diseases Infectious Diseases/Bacterial Infections Infectious Diseases/Gastrointestinal Infections Infectious Diseases/Tropical and Travel-Associated Diseases Intracellular Signaling Peptides and Proteins - metabolism Kinases Life Sciences Microbiology and Parasitology Microbiology/Parasitology Molecular Biology NEDD8 Protein Nuclei Pathogenic microorganisms Pathogens Physiological aspects proteasomes Protein Transport Proteins Rats scaffolds Signal Transduction SKP Cullin F-Box Protein Ligases - metabolism Subcellular Processes Symbiosis Toxins Transcription Two-Hybrid System Techniques Ubiquitin Ubiquitin-protein ligase Ubiquitination Ubiquitins - genetics Ubiquitins - metabolism virulence factors |
title | Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways |
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