Enzymatic Blockade of the Ubiquitin-Proteasome Pathway
Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrate...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2011
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| Online Access: | http://hdl.handle.net/1721.1/65337 https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826217473155792896 |
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| author | Ernst, Robert Claessen, Jasper H. L. Mueller, Britta Sanyal, Sumana Spooner, Eric van der Veen, Annemarthe G. Kirak, Oktay Schlieker, Christian D. Weihofen, Wilhelm A. Ploegh, Hidde |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ernst, Robert Claessen, Jasper H. L. Mueller, Britta Sanyal, Sumana Spooner, Eric van der Veen, Annemarthe G. Kirak, Oktay Schlieker, Christian D. Weihofen, Wilhelm A. Ploegh, Hidde |
| author_sort | Ernst, Robert |
| collection | MIT |
| description | Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity. |
| first_indexed | 2024-09-23T17:04:12Z |
| format | Article |
| id | mit-1721.1/65337 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:04:12Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/653372022-09-29T23:28:48Z Enzymatic Blockade of the Ubiquitin-Proteasome Pathway Ernst, Robert Claessen, Jasper H. L. Mueller, Britta Sanyal, Sumana Spooner, Eric van der Veen, Annemarthe G. Kirak, Oktay Schlieker, Christian D. Weihofen, Wilhelm A. Ploegh, Hidde Massachusetts Institute of Technology. Department of Biology Ploegh, Hidde Ploegh, Hidde Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity. National Institutes of Health (U.S.) EMBO (long term Fellowship 2008-379) Boehringer Ingelheim Fonds 2011-08-19T14:46:58Z 2011-08-19T14:46:58Z 2011-03 2010-08 Article http://purl.org/eprint/type/JournalArticle 1544-9173 1545-7885 http://hdl.handle.net/1721.1/65337 Ernst, Robert et al. “Enzymatic Blockade of the Ubiquitin-Proteasome Pathway.” Ed. Jonathan D. Ashwell. PLoS Biology 8.3 (2011) : e1000605. 21468303 https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.1371/journal.pbio.1000605 PLoS Biology Creative Commons Attribution http://creativecommons.org/licenses/by/2.5 application/pdf Public Library of Science PLoS |
| spellingShingle | Ernst, Robert Claessen, Jasper H. L. Mueller, Britta Sanyal, Sumana Spooner, Eric van der Veen, Annemarthe G. Kirak, Oktay Schlieker, Christian D. Weihofen, Wilhelm A. Ploegh, Hidde Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title | Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title_full | Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title_fullStr | Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title_full_unstemmed | Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title_short | Enzymatic Blockade of the Ubiquitin-Proteasome Pathway |
| title_sort | enzymatic blockade of the ubiquitin proteasome pathway |
| url | http://hdl.handle.net/1721.1/65337 https://orcid.org/0000-0002-1090-6071 |
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