Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy
Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and t...
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| Veröffentlicht in: | Autophagy 2015, Vol.11 (9), p.1458-1470 |
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| creator | Drießen, Stefan Berleth, Niklas Friesen, Olena Löffler, Antje S Böhler, Philip Hieke, Nora Stuhldreier, Fabian Peter, Christoph Schink, Kay O Schultz, Sebastian W Stenmark, Harald Holland, Petter Simonsen, Anne Wesselborg, Sebastian Stork, Björn |
| description | Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy. |
| doi_str_mv | 10.1080/15548627.2015.1067359 |
| format | Article |
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In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy.</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.1080/15548627.2015.1067359</identifier><identifier>PMID: 26207339</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Autophagy - drug effects ; Autophagy-Related Protein-1 Homolog ; Basic Brief Report ; Cyanoacrylates - pharmacology ; Green Fluorescent Proteins - metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins - metabolism ; Protein Aggregates - drug effects ; Protein-Serine-Threonine Kinases - metabolism ; Pyridines - pharmacology ; Ubiquitin-Specific Proteases - antagonists & inhibitors ; Ubiquitination - drug effects</subject><ispartof>Autophagy, 2015, Vol.11 (9), p.1458-1470</ispartof><rights>2015 Taylor & Francis Group, LLC 2015 Taylor & Francis Group, LLC</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-b26884564bd802b1e06221170f48cf3255537ae549cc960faecff9a87e967a393</citedby><cites>FETCH-LOGICAL-c477t-b26884564bd802b1e06221170f48cf3255537ae549cc960faecff9a87e967a393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590650/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590650/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,4021,27921,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26207339$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Drießen, Stefan</creatorcontrib><creatorcontrib>Berleth, Niklas</creatorcontrib><creatorcontrib>Friesen, Olena</creatorcontrib><creatorcontrib>Löffler, Antje S</creatorcontrib><creatorcontrib>Böhler, Philip</creatorcontrib><creatorcontrib>Hieke, Nora</creatorcontrib><creatorcontrib>Stuhldreier, Fabian</creatorcontrib><creatorcontrib>Peter, Christoph</creatorcontrib><creatorcontrib>Schink, Kay O</creatorcontrib><creatorcontrib>Schultz, Sebastian W</creatorcontrib><creatorcontrib>Stenmark, Harald</creatorcontrib><creatorcontrib>Holland, Petter</creatorcontrib><creatorcontrib>Simonsen, Anne</creatorcontrib><creatorcontrib>Wesselborg, Sebastian</creatorcontrib><creatorcontrib>Stork, Björn</creatorcontrib><title>Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy.</description><subject>Autophagy - drug effects</subject><subject>Autophagy-Related Protein-1 Homolog</subject><subject>Basic Brief Report</subject><subject>Cyanoacrylates - pharmacology</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Protein Aggregates - drug effects</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Pyridines - pharmacology</subject><subject>Ubiquitin-Specific Proteases - antagonists & inhibitors</subject><subject>Ubiquitination - drug effects</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkclOwzAQhi0EYn8EkI9cCl7i7YKE2EUlOFD1aE0cJzWkcYkTpL49KZQKTrP9889IH0InlJxToskFFSLTkqlzRqgYWlJxYbbQ_qo_0pKL7U3O1B46SOmNEC61Ybtoj0lGFOdmH01vfJ-Hjz50oYHkcWhmIR-K2OB8iacvlHKCaw9Fwl3Ek_ETxVBVra_gWwNNgfM6uncoPI4lhr6LixlUyyO0U0Kd_PE6HqLJ3e3r9cNo_Hz_eH01HrlMqW6UM6l1JmSWF5qwnHoiGaNUkTLTruRMCMEVeJEZ54wkJXhXlga08kYq4IYfossf30Wfz33hfNO1UNtFG-bQLm2EYP9PmjCzVfy0mTBECjIYnK0N2vjR-9TZeUjO1zU0PvbJUkW5EYQyOUjFj9S1MaXWl5szlNgVFPsLxa6g2DWUYe_074-brV8K_As6e4du</recordid><startdate>2015</startdate><enddate>2015</enddate><creator>Drießen, Stefan</creator><creator>Berleth, Niklas</creator><creator>Friesen, Olena</creator><creator>Löffler, Antje S</creator><creator>Böhler, Philip</creator><creator>Hieke, Nora</creator><creator>Stuhldreier, Fabian</creator><creator>Peter, Christoph</creator><creator>Schink, Kay O</creator><creator>Schultz, Sebastian W</creator><creator>Stenmark, Harald</creator><creator>Holland, Petter</creator><creator>Simonsen, Anne</creator><creator>Wesselborg, Sebastian</creator><creator>Stork, Björn</creator><general>Taylor & Francis</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>2015</creationdate><title>Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy</title><author>Drießen, Stefan ; Berleth, Niklas ; Friesen, Olena ; Löffler, Antje S ; Böhler, Philip ; Hieke, Nora ; Stuhldreier, Fabian ; Peter, Christoph ; Schink, Kay O ; Schultz, Sebastian W ; Stenmark, Harald ; Holland, Petter ; Simonsen, Anne ; Wesselborg, Sebastian ; Stork, Björn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-b26884564bd802b1e06221170f48cf3255537ae549cc960faecff9a87e967a393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Autophagy - drug effects</topic><topic>Autophagy-Related Protein-1 Homolog</topic><topic>Basic Brief Report</topic><topic>Cyanoacrylates - pharmacology</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Protein Aggregates - drug effects</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Pyridines - pharmacology</topic><topic>Ubiquitin-Specific Proteases - antagonists & inhibitors</topic><topic>Ubiquitination - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Drießen, Stefan</creatorcontrib><creatorcontrib>Berleth, Niklas</creatorcontrib><creatorcontrib>Friesen, Olena</creatorcontrib><creatorcontrib>Löffler, Antje S</creatorcontrib><creatorcontrib>Böhler, Philip</creatorcontrib><creatorcontrib>Hieke, Nora</creatorcontrib><creatorcontrib>Stuhldreier, Fabian</creatorcontrib><creatorcontrib>Peter, Christoph</creatorcontrib><creatorcontrib>Schink, Kay O</creatorcontrib><creatorcontrib>Schultz, Sebastian W</creatorcontrib><creatorcontrib>Stenmark, Harald</creatorcontrib><creatorcontrib>Holland, Petter</creatorcontrib><creatorcontrib>Simonsen, Anne</creatorcontrib><creatorcontrib>Wesselborg, Sebastian</creatorcontrib><creatorcontrib>Stork, Björn</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Drießen, Stefan</au><au>Berleth, Niklas</au><au>Friesen, Olena</au><au>Löffler, Antje S</au><au>Böhler, Philip</au><au>Hieke, Nora</au><au>Stuhldreier, Fabian</au><au>Peter, Christoph</au><au>Schink, Kay O</au><au>Schultz, Sebastian W</au><au>Stenmark, Harald</au><au>Holland, Petter</au><au>Simonsen, Anne</au><au>Wesselborg, Sebastian</au><au>Stork, Björn</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2015</date><risdate>2015</risdate><volume>11</volume><issue>9</issue><spage>1458</spage><epage>1470</epage><pages>1458-1470</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. 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| ispartof | Autophagy, 2015, Vol.11 (9), p.1458-1470 |
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| subjects | Autophagy - drug effects Autophagy-Related Protein-1 Homolog Basic Brief Report Cyanoacrylates - pharmacology Green Fluorescent Proteins - metabolism HEK293 Cells HeLa Cells Humans Intracellular Signaling Peptides and Proteins - metabolism Protein Aggregates - drug effects Protein-Serine-Threonine Kinases - metabolism Pyridines - pharmacology Ubiquitin-Specific Proteases - antagonists & inhibitors Ubiquitination - drug effects |
| title | Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy |
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