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Host Cell Factor Requirement for Hepatitis C Virus Enzyme Maturation
The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.13931-13935 |
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| cites | cdi_FETCH-LOGICAL-c586t-1fdc50d674142ce0a159160066071a63a7b2817023accc807cad87494e2d9b163 |
| container_end_page | 13935 |
| container_issue | 24 |
| container_start_page | 13931 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 98 |
| creator | Waxman, Lloyd Whitney, Michael Pollok, Brian A. Kuo, Lawrence C. Darke, Paul L. |
| description | The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable ATP analogs. Geldanamycin and radicicol, ATP-competitive inhibitors of the chaperone HSP90, also inhibit the cleavage of in vitro-synthesized NS2/3. Furthermore, these HSP90 inhibitors prevent NS2/3 cleavage when the protease is expressed in mammalian cells. The physical association of NS2/3 with HSP90 is demonstrated by immunoprecipitation. Thus, by way of a chaperone/folding activity, an HSP90-containing complex is required for maturation of the polyprotein that encodes the enzymes essential for hepatitis C virus replication. |
| doi_str_mv | 10.1073/pnas.241510898 |
| format | article |
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The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable ATP analogs. Geldanamycin and radicicol, ATP-competitive inhibitors of the chaperone HSP90, also inhibit the cleavage of in vitro-synthesized NS2/3. Furthermore, these HSP90 inhibitors prevent NS2/3 cleavage when the protease is expressed in mammalian cells. The physical association of NS2/3 with HSP90 is demonstrated by immunoprecipitation. 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The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable ATP analogs. Geldanamycin and radicicol, ATP-competitive inhibitors of the chaperone HSP90, also inhibit the cleavage of in vitro-synthesized NS2/3. Furthermore, these HSP90 inhibitors prevent NS2/3 cleavage when the protease is expressed in mammalian cells. The physical association of NS2/3 with HSP90 is demonstrated by immunoprecipitation. Thus, by way of a chaperone/folding activity, an HSP90-containing complex is required for maturation of the polyprotein that encodes the enzymes essential for hepatitis C virus replication.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Antibodies</subject><subject>Benzoquinones</subject><subject>Biological Sciences</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Enzymes</subject><subject>Gels</subject><subject>Hepacivirus</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C virus</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Hsp90 protein</subject><subject>Humans</subject><subject>Inhibitory concentration 50</subject><subject>Jurkat Cells</subject><subject>Lactams, Macrocyclic</subject><subject>Lactones - pharmacology</subject><subject>Low molecular weights</subject><subject>Macrolides</subject><subject>NS2/3 protein</subject><subject>Plasmids</subject><subject>Protein Processing, Post-Translational</subject><subject>Proteins</subject><subject>Quinones - metabolism</subject><subject>Quinones - pharmacology</subject><subject>RNA</subject><subject>Ubiquitins</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNqFkUuLFDEUhYMoTju6dSVazELcVHtvksoDZiPtjC2MCKJuQzqV0mrq0ZOkZMZfb4pu28dCVyGc71zOvYeQxwhLBMle7gYbl5RjhaC0ukMWCBpLwTXcJQsAKkvFKT8hD2LcAoCuFNwnJ4gSZKX5grxejzEVK991xaV1aQzFB389tcH3fkhFk_9rv7OpTW0sVsXnNkyxuBi-3_a-eGfTFLI0Dg_JvcZ20T86vKfk0-XFx9W6vHr_5u3q1VXpKiVSiU3tKqiF5Mip82Cx0igAhACJVjArN1TlZJRZ55wC6WytJNfc01pvULBTcr6fu5s2va9djhhsZ3ah7W24NaNtzZ_K0H41X8ZvRiBynu3PD_YwXk8-JtO30eXV7eDHKRpJqVa80v8FUSGVjM4Tz_4Ct-MUhnwDQwGZyAvO0HIPuTDGGHxzDIxg5hLNXKI5lpgNT39f8xd-aC0Dzw7AbPwpa5VnGGSaYSZe_JswzdR1yd-kjD7Zo9uY6z-yDCqJWrIfHxS4vA</recordid><startdate>20011120</startdate><enddate>20011120</enddate><creator>Waxman, Lloyd</creator><creator>Whitney, Michael</creator><creator>Pollok, Brian A.</creator><creator>Kuo, Lawrence C.</creator><creator>Darke, Paul L.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20011120</creationdate><title>Host Cell Factor Requirement for Hepatitis C Virus Enzyme Maturation</title><author>Waxman, Lloyd ; Whitney, Michael ; Pollok, Brian A. ; Kuo, Lawrence C. ; Darke, Paul L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c586t-1fdc50d674142ce0a159160066071a63a7b2817023accc807cad87494e2d9b163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Antibodies</topic><topic>Benzoquinones</topic><topic>Biological Sciences</topic><topic>Cysteine Endopeptidases - genetics</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Enzymes</topic><topic>Gels</topic><topic>Hepacivirus</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis</topic><topic>Hepatitis C</topic><topic>Hepatitis C virus</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Hsp90 protein</topic><topic>Humans</topic><topic>Inhibitory concentration 50</topic><topic>Jurkat Cells</topic><topic>Lactams, Macrocyclic</topic><topic>Lactones - pharmacology</topic><topic>Low molecular weights</topic><topic>Macrolides</topic><topic>NS2/3 protein</topic><topic>Plasmids</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteins</topic><topic>Quinones - metabolism</topic><topic>Quinones - pharmacology</topic><topic>RNA</topic><topic>Ubiquitins</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Waxman, Lloyd</creatorcontrib><creatorcontrib>Whitney, Michael</creatorcontrib><creatorcontrib>Pollok, Brian A.</creatorcontrib><creatorcontrib>Kuo, Lawrence C.</creatorcontrib><creatorcontrib>Darke, Paul L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Waxman, Lloyd</au><au>Whitney, Michael</au><au>Pollok, Brian A.</au><au>Kuo, Lawrence C.</au><au>Darke, Paul L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Host Cell Factor Requirement for Hepatitis C Virus Enzyme Maturation</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2001-11-20</date><risdate>2001</risdate><volume>98</volume><issue>24</issue><spage>13931</spage><epage>13935</epage><pages>13931-13935</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2001-11, Vol.98 (24), p.13931-13935 |
| issn | 0027-8424 1091-6490 |
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| source | Open Access: PubMed Central; JSTOR Archival Journals and Primary Sources Collection |
| subjects | Adenosine Triphosphate - metabolism Antibodies Benzoquinones Biological Sciences Cysteine Endopeptidases - genetics Cysteine Endopeptidases - metabolism Enzymes Gels Hepacivirus Hepacivirus - enzymology Hepatitis Hepatitis C Hepatitis C virus HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Humans Inhibitory concentration 50 Jurkat Cells Lactams, Macrocyclic Lactones - pharmacology Low molecular weights Macrolides NS2/3 protein Plasmids Protein Processing, Post-Translational Proteins Quinones - metabolism Quinones - pharmacology RNA Ubiquitins Viruses |
| title | Host Cell Factor Requirement for Hepatitis C Virus Enzyme Maturation |
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