trappc11 is required for protein glycosylation in zebrafish and humans
Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which en...
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| Veröffentlicht in: | Molecular biology of the cell 2016-04, Vol.27 (8), p.1220-1234 |
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| creator | DeRossi, Charles Vacaru, Ana Rafiq, Ruhina Cinaroglu, Ayca Imrie, Dru Nayar, Shikha Baryshnikova, Anastasia Milev, Miroslav P Stanga, Daniela Kadakia, Dhara Gao, Ningguo Chu, Jaime Freeze, Hudson H Lehrman, Mark A Sacher, Michael Sadler, Kirsten C |
| description | Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with theTRAPPC11mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking. |
| doi_str_mv | 10.1091/mbc.E15-08-0557 |
| format | Article |
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We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with theTRAPPC11mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.</description><identifier>ISSN: 1059-1524</identifier><identifier>EISSN: 1939-4586</identifier><identifier>DOI: 10.1091/mbc.E15-08-0557</identifier><identifier>PMID: 26912795</identifier><language>eng</language><publisher>United States: The American Society for Cell Biology</publisher><subject>Animals ; Animals, Genetically Modified ; Atorvastatin - pharmacology ; Dolichol - biosynthesis ; Dolichol - genetics ; Glycosylation ; Golgi Apparatus - genetics ; Golgi Apparatus - metabolism ; Humans ; Larva - drug effects ; Larva - metabolism ; Lipids - chemistry ; Liver - metabolism ; Liver - pathology ; Mutation ; Oligosaccharides - chemistry ; Oligosaccharides - metabolism ; Terpenes - metabolism ; Terpenes - pharmacology ; Unfolded Protein Response - drug effects ; Unfolded Protein Response - genetics ; Vesicular Transport Proteins - genetics ; Vesicular Transport Proteins - metabolism ; Zebrafish - genetics ; Zebrafish Proteins - genetics ; Zebrafish Proteins - metabolism</subject><ispartof>Molecular biology of the cell, 2016-04, Vol.27 (8), p.1220-1234</ispartof><rights>2016 DeRossi, Vacaru, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).</rights><rights>2016 DeRossi, Vacaru, This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( ). 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-35d65686b817da8177fbe862f2847b9d29084697cb2a93d7450eb91c817c20c3</citedby><cites>FETCH-LOGICAL-c398t-35d65686b817da8177fbe862f2847b9d29084697cb2a93d7450eb91c817c20c3</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/PMC4831877/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831877/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26912795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DeRossi, Charles</creatorcontrib><creatorcontrib>Vacaru, Ana</creatorcontrib><creatorcontrib>Rafiq, Ruhina</creatorcontrib><creatorcontrib>Cinaroglu, Ayca</creatorcontrib><creatorcontrib>Imrie, Dru</creatorcontrib><creatorcontrib>Nayar, Shikha</creatorcontrib><creatorcontrib>Baryshnikova, Anastasia</creatorcontrib><creatorcontrib>Milev, Miroslav P</creatorcontrib><creatorcontrib>Stanga, Daniela</creatorcontrib><creatorcontrib>Kadakia, Dhara</creatorcontrib><creatorcontrib>Gao, Ningguo</creatorcontrib><creatorcontrib>Chu, Jaime</creatorcontrib><creatorcontrib>Freeze, Hudson H</creatorcontrib><creatorcontrib>Lehrman, Mark A</creatorcontrib><creatorcontrib>Sacher, Michael</creatorcontrib><creatorcontrib>Sadler, Kirsten C</creatorcontrib><title>trappc11 is required for protein glycosylation in zebrafish and humans</title><title>Molecular biology of the cell</title><addtitle>Mol Biol Cell</addtitle><description>Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with theTRAPPC11mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.</description><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Atorvastatin - pharmacology</subject><subject>Dolichol - biosynthesis</subject><subject>Dolichol - genetics</subject><subject>Glycosylation</subject><subject>Golgi Apparatus - genetics</subject><subject>Golgi Apparatus - metabolism</subject><subject>Humans</subject><subject>Larva - drug effects</subject><subject>Larva - metabolism</subject><subject>Lipids - chemistry</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Mutation</subject><subject>Oligosaccharides - chemistry</subject><subject>Oligosaccharides - metabolism</subject><subject>Terpenes - metabolism</subject><subject>Terpenes - pharmacology</subject><subject>Unfolded Protein Response - drug effects</subject><subject>Unfolded Protein Response - genetics</subject><subject>Vesicular Transport Proteins - genetics</subject><subject>Vesicular Transport Proteins - metabolism</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish Proteins - genetics</subject><subject>Zebrafish Proteins - metabolism</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1LAzEQhoMotlbP3iR_YNskm8-LIKVVoeCl95Bks21kv0xaof56U6pFLzPDzDvvDA8A9xhNMVJ41lo3XWBWIFkgxsQFGGNVqoIyyS9zjZgqMCN0BG5SekcIU8rFNRgRrjARio3BchfNMDiMYUgw-o99iL6CdR_hEPudDx3cNAfXp0NjdqHvYG58eRtNHdIWmq6C231runQLrmrTJH_3kydgvVys5y_F6u35df60Klyp5K4oWcUZl9xKLCqTg6itl5zURFJhVUUUkpQr4SwxqqwEZchbhV1WOoJcOQGPJ9thb1tfOd_l9xs9xNCaeNC9Cfr_pAtbvek_NZUllkJkg9nJwMU-pejr8y5G-khUZ6I6E9VI6iPRvPHw9-RZ_4uw_AaJHHNt</recordid><startdate>20160415</startdate><enddate>20160415</enddate><creator>DeRossi, Charles</creator><creator>Vacaru, Ana</creator><creator>Rafiq, Ruhina</creator><creator>Cinaroglu, Ayca</creator><creator>Imrie, Dru</creator><creator>Nayar, Shikha</creator><creator>Baryshnikova, Anastasia</creator><creator>Milev, Miroslav P</creator><creator>Stanga, Daniela</creator><creator>Kadakia, Dhara</creator><creator>Gao, Ningguo</creator><creator>Chu, Jaime</creator><creator>Freeze, Hudson H</creator><creator>Lehrman, Mark A</creator><creator>Sacher, Michael</creator><creator>Sadler, Kirsten C</creator><general>The American Society for Cell Biology</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>5PM</scope></search><sort><creationdate>20160415</creationdate><title>trappc11 is required for protein glycosylation in zebrafish and humans</title><author>DeRossi, Charles ; Vacaru, Ana ; Rafiq, Ruhina ; Cinaroglu, Ayca ; Imrie, Dru ; Nayar, Shikha ; Baryshnikova, Anastasia ; Milev, Miroslav P ; Stanga, Daniela ; Kadakia, Dhara ; Gao, Ningguo ; Chu, Jaime ; Freeze, Hudson H ; Lehrman, Mark A ; Sacher, Michael ; Sadler, Kirsten C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-35d65686b817da8177fbe862f2847b9d29084697cb2a93d7450eb91c817c20c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Atorvastatin - pharmacology</topic><topic>Dolichol - biosynthesis</topic><topic>Dolichol - genetics</topic><topic>Glycosylation</topic><topic>Golgi Apparatus - genetics</topic><topic>Golgi Apparatus - metabolism</topic><topic>Humans</topic><topic>Larva - drug effects</topic><topic>Larva - metabolism</topic><topic>Lipids - chemistry</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Mutation</topic><topic>Oligosaccharides - chemistry</topic><topic>Oligosaccharides - metabolism</topic><topic>Terpenes - metabolism</topic><topic>Terpenes - pharmacology</topic><topic>Unfolded Protein Response - drug effects</topic><topic>Unfolded Protein Response - genetics</topic><topic>Vesicular Transport Proteins - genetics</topic><topic>Vesicular Transport Proteins - metabolism</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish Proteins - genetics</topic><topic>Zebrafish Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DeRossi, Charles</creatorcontrib><creatorcontrib>Vacaru, Ana</creatorcontrib><creatorcontrib>Rafiq, Ruhina</creatorcontrib><creatorcontrib>Cinaroglu, Ayca</creatorcontrib><creatorcontrib>Imrie, Dru</creatorcontrib><creatorcontrib>Nayar, Shikha</creatorcontrib><creatorcontrib>Baryshnikova, Anastasia</creatorcontrib><creatorcontrib>Milev, Miroslav P</creatorcontrib><creatorcontrib>Stanga, Daniela</creatorcontrib><creatorcontrib>Kadakia, Dhara</creatorcontrib><creatorcontrib>Gao, Ningguo</creatorcontrib><creatorcontrib>Chu, Jaime</creatorcontrib><creatorcontrib>Freeze, Hudson H</creatorcontrib><creatorcontrib>Lehrman, Mark A</creatorcontrib><creatorcontrib>Sacher, Michael</creatorcontrib><creatorcontrib>Sadler, Kirsten C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DeRossi, Charles</au><au>Vacaru, Ana</au><au>Rafiq, Ruhina</au><au>Cinaroglu, Ayca</au><au>Imrie, Dru</au><au>Nayar, Shikha</au><au>Baryshnikova, Anastasia</au><au>Milev, Miroslav P</au><au>Stanga, Daniela</au><au>Kadakia, Dhara</au><au>Gao, Ningguo</au><au>Chu, Jaime</au><au>Freeze, Hudson H</au><au>Lehrman, Mark A</au><au>Sacher, Michael</au><au>Sadler, Kirsten C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>trappc11 is required for protein glycosylation in zebrafish and humans</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2016-04-15</date><risdate>2016</risdate><volume>27</volume><issue>8</issue><spage>1220</spage><epage>1234</epage><pages>1220-1234</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with theTRAPPC11mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.</abstract><cop>United States</cop><pub>The American Society for Cell Biology</pub><pmid>26912795</pmid><doi>10.1091/mbc.E15-08-0557</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Animals, Genetically Modified Atorvastatin - pharmacology Dolichol - biosynthesis Dolichol - genetics Glycosylation Golgi Apparatus - genetics Golgi Apparatus - metabolism Humans Larva - drug effects Larva - metabolism Lipids - chemistry Liver - metabolism Liver - pathology Mutation Oligosaccharides - chemistry Oligosaccharides - metabolism Terpenes - metabolism Terpenes - pharmacology Unfolded Protein Response - drug effects Unfolded Protein Response - genetics Vesicular Transport Proteins - genetics Vesicular Transport Proteins - metabolism Zebrafish - genetics Zebrafish Proteins - genetics Zebrafish Proteins - metabolism |
| title | trappc11 is required for protein glycosylation in zebrafish and humans |
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