KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome

Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be ess...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2014, Vol.9 (3), p.e91359-e91359
Main Authors: Ehrlich, Elana S, Chmura, Jennifer C, Smith, John C, Kalu, Nene N, Hayward, Gary S
Format: Article
Language:English
Subjects:
Activation
Animals
Apoptosis
Biology
Cancer
CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism
Castleman's disease
Cell survival
Chlorocebus aethiops
Degradation
Destabilization
Doxycycline
Effusion
Gene expression
Gene Expression Regulation
Genomics
HEK293 Cells
Herpesvirus 8, Human - metabolism
Humans
Infections
Intercellular adhesion molecule 1
Intercellular Adhesion Molecule-1 - genetics
Intercellular Adhesion Molecule-1 - metabolism
Kaposi's sarcoma
Kaposis sarcoma
Kinases
Latent infection
Lymphoma
Mutants
NF-kappa B - metabolism
NF-κB protein
Oncology
Plasmids
Primary effusion lymphoma
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Proteins
Proteolysis
Sarcoma
Trans-Activators - metabolism
Transcription factors
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Up-Regulation
Vero Cells
Viral infections
Virus Activation - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23
cites cdi_FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23
container_end_page e91359
container_issue 3
container_start_page e91359
container_title PloS one
container_volume 9
creator Ehrlich, Elana S
Chmura, Jennifer C
Smith, John C
Kalu, Nene N
Hayward, Gary S
description Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NFĸB pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NFκB activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NFĸB responsive genes ICAM1 and TNFα, inclusion of RTA decreased vFLIP induced ICAM1 and TNFα expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NFĸB responsive gene expression early during lytic reactivation.
doi_str_mv 10.1371/journal.pone.0091359
format article
fullrecord <record><control><sourceid>proquest_plos_</sourceid><recordid>TN_cdi_plos_journals_1506075605</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_6789894e3b4c4776b21aafd0fd7ddea0</doaj_id><sourcerecordid>1506791929</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23</originalsourceid><addsrcrecordid>eNptUsFuEzEQXSEQbQN_gMASl14S7LV3vb4glYrQiAgQFK7W2J7dONqsg72JyJm_4iP4JjYkrVrEaax5b57njV6WPWN0wrhkr5ZhEztoJ-vQ4YRSxXihHmSnTPF8XOaUP7zzPsnOUlpSWvCqLB9nJ7komSgqeZr9fP_l6hv5fH1BwITWpwUm8mH6-9cbEjEN0slvkTTYIcEf66GVfOiI20TfNaTd9d4OPLC930K_R8yO9BAb7Pf4djqffSJ1iMRhE8EdKFsPpF8gWcfQI6SwwifZoxrahE-PdZR9nb69vrwazz--m11ezMd28KvGjtfKgZSVrIsclIRqKNLYnFuUsubG1FCpvMg5s8Zw5yq0oqBVIYQwAnM-yl4cdNdtSPp4v6RZQUsqi3K4ziibHRguwFKvo19B3OkAXv9thNhoiIPpFnUpK1UpgdwIK6QsTc4AakdrJ51DoIPW6-NvG7NCZ7HrI7T3RO8jnV_oJmw1V6KqxH7d86NADN83mHq98sli20KHYXPYWyqmcjVQX_5D_b87cWDZGFKKWN8uw6jeZ-pmSu8zpY-ZGsae3zVyO3QTIv4HNb7NYA</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1506075605</pqid></control><display><type>article</type><title>KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome</title><source>PMC (PubMed Central)</source><source>Publicly Available Content (ProQuest)</source><creator>Ehrlich, Elana S ; Chmura, Jennifer C ; Smith, John C ; Kalu, Nene N ; Hayward, Gary S</creator><creatorcontrib>Ehrlich, Elana S ; Chmura, Jennifer C ; Smith, John C ; Kalu, Nene N ; Hayward, Gary S</creatorcontrib><description>Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NFĸB pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NFκB activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NFĸB responsive genes ICAM1 and TNFα, inclusion of RTA decreased vFLIP induced ICAM1 and TNFα expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NFĸB responsive gene expression early during lytic reactivation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0091359</identifier><identifier>PMID: 24614587</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Animals ; Apoptosis ; Biology ; Cancer ; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism ; Castleman's disease ; Cell survival ; Chlorocebus aethiops ; Degradation ; Destabilization ; Doxycycline ; Effusion ; Gene expression ; Gene Expression Regulation ; Genomics ; HEK293 Cells ; Herpesvirus 8, Human - metabolism ; Humans ; Infections ; Intercellular adhesion molecule 1 ; Intercellular Adhesion Molecule-1 - genetics ; Intercellular Adhesion Molecule-1 - metabolism ; Kaposi's sarcoma ; Kaposis sarcoma ; Kinases ; Latent infection ; Lymphoma ; Mutants ; NF-kappa B - metabolism ; NF-κB protein ; Oncology ; Plasmids ; Primary effusion lymphoma ; Proteasome Endopeptidase Complex - metabolism ; Proteasomes ; Proteins ; Proteolysis ; Sarcoma ; Trans-Activators - metabolism ; Transcription factors ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - metabolism ; Up-Regulation ; Vero Cells ; Viral infections ; Virus Activation - genetics</subject><ispartof>PloS one, 2014, Vol.9 (3), p.e91359-e91359</ispartof><rights>2014 Ehrlich et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Ehrlich et al 2014 Ehrlich et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23</citedby><cites>FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1506075605/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1506075605?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,25731,27900,27901,27902,36989,36990,44566,53766,53768,74869</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24614587$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ehrlich, Elana S</creatorcontrib><creatorcontrib>Chmura, Jennifer C</creatorcontrib><creatorcontrib>Smith, John C</creatorcontrib><creatorcontrib>Kalu, Nene N</creatorcontrib><creatorcontrib>Hayward, Gary S</creatorcontrib><title>KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NFĸB pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NFκB activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NFĸB responsive genes ICAM1 and TNFα, inclusion of RTA decreased vFLIP induced ICAM1 and TNFα expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NFĸB responsive gene expression early during lytic reactivation.</description><subject>Activation</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Cancer</subject><subject>CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism</subject><subject>Castleman's disease</subject><subject>Cell survival</subject><subject>Chlorocebus aethiops</subject><subject>Degradation</subject><subject>Destabilization</subject><subject>Doxycycline</subject><subject>Effusion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genomics</subject><subject>HEK293 Cells</subject><subject>Herpesvirus 8, Human - metabolism</subject><subject>Humans</subject><subject>Infections</subject><subject>Intercellular adhesion molecule 1</subject><subject>Intercellular Adhesion Molecule-1 - genetics</subject><subject>Intercellular Adhesion Molecule-1 - metabolism</subject><subject>Kaposi's sarcoma</subject><subject>Kaposis sarcoma</subject><subject>Kinases</subject><subject>Latent infection</subject><subject>Lymphoma</subject><subject>Mutants</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Oncology</subject><subject>Plasmids</subject><subject>Primary effusion lymphoma</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteasomes</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Sarcoma</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription factors</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Up-Regulation</subject><subject>Vero Cells</subject><subject>Viral infections</subject><subject>Virus Activation - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptUsFuEzEQXSEQbQN_gMASl14S7LV3vb4glYrQiAgQFK7W2J7dONqsg72JyJm_4iP4JjYkrVrEaax5b57njV6WPWN0wrhkr5ZhEztoJ-vQ4YRSxXihHmSnTPF8XOaUP7zzPsnOUlpSWvCqLB9nJ7komSgqeZr9fP_l6hv5fH1BwITWpwUm8mH6-9cbEjEN0slvkTTYIcEf66GVfOiI20TfNaTd9d4OPLC930K_R8yO9BAb7Pf4djqffSJ1iMRhE8EdKFsPpF8gWcfQI6SwwifZoxrahE-PdZR9nb69vrwazz--m11ezMd28KvGjtfKgZSVrIsclIRqKNLYnFuUsubG1FCpvMg5s8Zw5yq0oqBVIYQwAnM-yl4cdNdtSPp4v6RZQUsqi3K4ziibHRguwFKvo19B3OkAXv9thNhoiIPpFnUpK1UpgdwIK6QsTc4AakdrJ51DoIPW6-NvG7NCZ7HrI7T3RO8jnV_oJmw1V6KqxH7d86NADN83mHq98sli20KHYXPYWyqmcjVQX_5D_b87cWDZGFKKWN8uw6jeZ-pmSu8zpY-ZGsae3zVyO3QTIv4HNb7NYA</recordid><startdate>2014</startdate><enddate>2014</enddate><creator>Ehrlich, Elana S</creator><creator>Chmura, Jennifer C</creator><creator>Smith, John C</creator><creator>Kalu, Nene N</creator><creator>Hayward, Gary S</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>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>AEUYN</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>2014</creationdate><title>KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome</title><author>Ehrlich, Elana S ; Chmura, Jennifer C ; Smith, John C ; Kalu, Nene N ; Hayward, Gary S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Activation</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Cancer</topic><topic>CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism</topic><topic>Castleman's disease</topic><topic>Cell survival</topic><topic>Chlorocebus aethiops</topic><topic>Degradation</topic><topic>Destabilization</topic><topic>Doxycycline</topic><topic>Effusion</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genomics</topic><topic>HEK293 Cells</topic><topic>Herpesvirus 8, Human - metabolism</topic><topic>Humans</topic><topic>Infections</topic><topic>Intercellular adhesion molecule 1</topic><topic>Intercellular Adhesion Molecule-1 - genetics</topic><topic>Intercellular Adhesion Molecule-1 - metabolism</topic><topic>Kaposi's sarcoma</topic><topic>Kaposis sarcoma</topic><topic>Kinases</topic><topic>Latent infection</topic><topic>Lymphoma</topic><topic>Mutants</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Oncology</topic><topic>Plasmids</topic><topic>Primary effusion lymphoma</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteasomes</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Sarcoma</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription factors</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Up-Regulation</topic><topic>Vero Cells</topic><topic>Viral infections</topic><topic>Virus Activation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ehrlich, Elana S</creatorcontrib><creatorcontrib>Chmura, Jennifer C</creatorcontrib><creatorcontrib>Smith, John C</creatorcontrib><creatorcontrib>Kalu, Nene N</creatorcontrib><creatorcontrib>Hayward, Gary S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ehrlich, Elana S</au><au>Chmura, Jennifer C</au><au>Smith, John C</au><au>Kalu, Nene N</au><au>Hayward, Gary S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e91359</spage><epage>e91359</epage><pages>e91359-e91359</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NFĸB pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NFκB activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NFĸB responsive genes ICAM1 and TNFα, inclusion of RTA decreased vFLIP induced ICAM1 and TNFα expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NFĸB responsive gene expression early during lytic reactivation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24614587</pmid><doi>10.1371/journal.pone.0091359</doi><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1932-6203
ispartof PloS one, 2014, Vol.9 (3), p.e91359-e91359
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1506075605
source PMC (PubMed Central); Publicly Available Content (ProQuest)
subjects Activation
Animals
Apoptosis
Biology
Cancer
CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism
Castleman's disease
Cell survival
Chlorocebus aethiops
Degradation
Destabilization
Doxycycline
Effusion
Gene expression
Gene Expression Regulation
Genomics
HEK293 Cells
Herpesvirus 8, Human - metabolism
Humans
Infections
Intercellular adhesion molecule 1
Intercellular Adhesion Molecule-1 - genetics
Intercellular Adhesion Molecule-1 - metabolism
Kaposi's sarcoma
Kaposis sarcoma
Kinases
Latent infection
Lymphoma
Mutants
NF-kappa B - metabolism
NF-κB protein
Oncology
Plasmids
Primary effusion lymphoma
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Proteins
Proteolysis
Sarcoma
Trans-Activators - metabolism
Transcription factors
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Up-Regulation
Vero Cells
Viral infections
Virus Activation - genetics
title KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T17%3A59%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=KSHV%20RTA%20abolishes%20NF%CE%BAB%20responsive%20gene%20expression%20during%20lytic%20reactivation%20by%20targeting%20vFLIP%20for%20degradation%20via%20the%20proteasome&rft.jtitle=PloS%20one&rft.au=Ehrlich,%20Elana%20S&rft.date=2014&rft.volume=9&rft.issue=3&rft.spage=e91359&rft.epage=e91359&rft.pages=e91359-e91359&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0091359&rft_dat=%3Cproquest_plos_%3E1506791929%3C/proquest_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c3719-d3f9da7787f52a97a852a7bc23ce77f3bbfa8925231cbb3dd8ec45085444b4e23%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1506075605&rft_id=info:pmid/24614587&rfr_iscdi=true