A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation
Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regul...
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| Veröffentlicht in: | PLoS pathogens 2013-03, Vol.9 (3), p.e1003273 |
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| creator | Ching, Wilhelm Koyuncu, Emre Singh, Sonia Arbelo-Roman, Christina Hartl, Barbara Kremmer, Elisabeth Speiseder, Thomas Meier, Chris Dobner, Thomas |
| description | Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies. |
| doi_str_mv | 10.1371/journal.ppat.1003273 |
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However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1003273</identifier><identifier>PMID: 23555268</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoviruses ; Adenoviruses, Human - pathogenicity ; Adenoviruses, Human - physiology ; Animals ; Binding Sites ; Biology ; Cell Proliferation ; Cell Transformation, Viral ; Cells, Cultured ; DNA replication ; Down-Regulation ; Endopeptidases - metabolism ; Enzymes ; Experiments ; Gene Silencing ; Genetic aspects ; Genetic transformation ; Health aspects ; Host-Pathogen Interactions ; Humans ; Mortality ; Physiological aspects ; Proteases ; Proteins ; ras Proteins - physiology ; Rats ; RNA, Small Interfering - genetics ; Ubiquitin ; Ubiquitin Thiolesterase - genetics ; Ubiquitin-Specific Peptidase 7 ; Ubiquitin-Specific Proteases ; Viral infections ; Virus Replication - physiology ; Viruses</subject><ispartof>PLoS pathogens, 2013-03, Vol.9 (3), p.e1003273</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Ching et al 2013 Ching et al</rights><rights>2013 Ching 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: Ching W, Koyuncu E, Singh S, Arbelo-Roman C, Hartl B, et al. (2013) A Ubiquitin-specific Protease Possesses a Decisive Role for Adenovirus Replication and Oncogene-mediated Transformation. 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However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies.</description><subject>Adenoviruses</subject><subject>Adenoviruses, Human - pathogenicity</subject><subject>Adenoviruses, Human - physiology</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Viral</subject><subject>Cells, Cultured</subject><subject>DNA replication</subject><subject>Down-Regulation</subject><subject>Endopeptidases - metabolism</subject><subject>Enzymes</subject><subject>Experiments</subject><subject>Gene Silencing</subject><subject>Genetic aspects</subject><subject>Genetic transformation</subject><subject>Health aspects</subject><subject>Host-Pathogen Interactions</subject><subject>Humans</subject><subject>Mortality</subject><subject>Physiological aspects</subject><subject>Proteases</subject><subject>Proteins</subject><subject>ras Proteins - physiology</subject><subject>Rats</subject><subject>RNA, Small Interfering - genetics</subject><subject>Ubiquitin</subject><subject>Ubiquitin Thiolesterase - genetics</subject><subject>Ubiquitin-Specific Peptidase 7</subject><subject>Ubiquitin-Specific Proteases</subject><subject>Viral infections</subject><subject>Virus Replication - physiology</subject><subject>Viruses</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVktuL1DAYxYMo7jr6H4gGfPKhYy5NLy_CsHgZWBS8PIc0-VIzdJKatKP-92Z2Zpct-CItNCS_c8L5ehB6Tsma8pq-2YU5ejWsx1FNa0oIZzV_gC6pELyoeV0-vLe-QE9S2hFSUk6rx-iCcSEEq5pL9GuD5879nN3kfJFG0M46jccYJlAJ8BhSguOLFTb5MLkD4BgGwDZErAz4cHBxTjjCODitJhc8Vt7g4HXowUOxB-PUBAZPUfmUVfsb6Cl6ZNWQ4Nn5u0Lf37_7dvWxuP78YXu1uS501bZT0QHYhuoGqDHGQlNVjFRc0JaUTaOhLEXO1BLWGKqooJwxUjcCTF3yzlLC-Qq9PPmOQ0jyPLMkM1nXvBWZW6HtiTBB7eQY3V7FPzIoJ282QuylipPTA8imstnbMspbXjLRdtpqA6oEAkaU9uj19nzb3OXgGnxOPSxMlyfe_ZB9OEheUVLnv7NCr04Gvcr3OW9DxvTeJS03nFU5LWvbTK3_QeXHwN7p4MG6vL8QvF4IMjPB76lXc0py-_XLf7Cflmx5YnXMRYlg76JSIo8tvZ24PLZUnluaZS_uj-lOdFtL_hcfX-Y4</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Ching, Wilhelm</creator><creator>Koyuncu, Emre</creator><creator>Singh, Sonia</creator><creator>Arbelo-Roman, Christina</creator><creator>Hartl, Barbara</creator><creator>Kremmer, Elisabeth</creator><creator>Speiseder, Thomas</creator><creator>Meier, Chris</creator><creator>Dobner, Thomas</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>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130301</creationdate><title>A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation</title><author>Ching, Wilhelm ; Koyuncu, Emre ; Singh, Sonia ; Arbelo-Roman, Christina ; Hartl, Barbara ; Kremmer, Elisabeth ; Speiseder, Thomas ; Meier, Chris ; Dobner, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c699t-beef81c8e1dddfe86620635190488ce4450419028d1a1513220785ed743bf1033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenoviruses</topic><topic>Adenoviruses, Human - pathogenicity</topic><topic>Adenoviruses, Human - physiology</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Biology</topic><topic>Cell Proliferation</topic><topic>Cell Transformation, Viral</topic><topic>Cells, Cultured</topic><topic>DNA replication</topic><topic>Down-Regulation</topic><topic>Endopeptidases - metabolism</topic><topic>Enzymes</topic><topic>Experiments</topic><topic>Gene Silencing</topic><topic>Genetic aspects</topic><topic>Genetic transformation</topic><topic>Health aspects</topic><topic>Host-Pathogen Interactions</topic><topic>Humans</topic><topic>Mortality</topic><topic>Physiological aspects</topic><topic>Proteases</topic><topic>Proteins</topic><topic>ras Proteins - physiology</topic><topic>Rats</topic><topic>RNA, Small Interfering - genetics</topic><topic>Ubiquitin</topic><topic>Ubiquitin Thiolesterase - genetics</topic><topic>Ubiquitin-Specific Peptidase 7</topic><topic>Ubiquitin-Specific Proteases</topic><topic>Viral infections</topic><topic>Virus Replication - physiology</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ching, Wilhelm</creatorcontrib><creatorcontrib>Koyuncu, Emre</creatorcontrib><creatorcontrib>Singh, Sonia</creatorcontrib><creatorcontrib>Arbelo-Roman, Christina</creatorcontrib><creatorcontrib>Hartl, Barbara</creatorcontrib><creatorcontrib>Kremmer, Elisabeth</creatorcontrib><creatorcontrib>Speiseder, Thomas</creatorcontrib><creatorcontrib>Meier, Chris</creatorcontrib><creatorcontrib>Dobner, Thomas</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>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ching, Wilhelm</au><au>Koyuncu, Emre</au><au>Singh, Sonia</au><au>Arbelo-Roman, Christina</au><au>Hartl, Barbara</au><au>Kremmer, Elisabeth</au><au>Speiseder, Thomas</au><au>Meier, Chris</au><au>Dobner, Thomas</au><au>Ornelles, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>9</volume><issue>3</issue><spage>e1003273</spage><pages>e1003273-</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23555268</pmid><doi>10.1371/journal.ppat.1003273</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoviruses Adenoviruses, Human - pathogenicity Adenoviruses, Human - physiology Animals Binding Sites Biology Cell Proliferation Cell Transformation, Viral Cells, Cultured DNA replication Down-Regulation Endopeptidases - metabolism Enzymes Experiments Gene Silencing Genetic aspects Genetic transformation Health aspects Host-Pathogen Interactions Humans Mortality Physiological aspects Proteases Proteins ras Proteins - physiology Rats RNA, Small Interfering - genetics Ubiquitin Ubiquitin Thiolesterase - genetics Ubiquitin-Specific Peptidase 7 Ubiquitin-Specific Proteases Viral infections Virus Replication - physiology Viruses |
| title | A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation |
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