Fine tuning of the UPR by the ubiquitin ligases Siah1/2
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell...
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| creator | Scortegagna, Marzia Kim, Hyungsoo Li, Jian-Liang Yao, Hang Brill, Laurence M Han, Jaeseok Lau, Eric Bowtell, David Haddad, Gabriel Kaufman, Randal J Ronai, Ze'ev A |
| description | The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions. |
| doi_str_mv | 10.1371/journal.pgen.1004348 |
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Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1004348</identifier><identifier>PMID: 24809345</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Apoptosis ; Biology and Life Sciences ; Cells, Cultured ; CHO Cells ; Cricetinae ; Cricetulus ; Endoplasmic reticulum ; Endoplasmic Reticulum - metabolism ; Enzyme Activation ; Experiments ; Genetic transcription ; Health aspects ; Heart attacks ; Homeostasis ; Humans ; Ischemia ; Isoenzymes - metabolism ; Kinases ; Ligases ; Medicine and Health Sciences ; Mice ; Protein folding ; Protein research ; Real-Time Polymerase Chain Reaction ; Regulation ; Research and Analysis Methods ; RNA, Messenger - genetics ; Rodents ; Stress response ; Stress, Physiological ; Transcription factors ; Transcription, Genetic ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Unfolded Protein Response</subject><ispartof>PLoS genetics, 2014-05, Vol.10 (5), p.e1004348-e1004348</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Scortegagna et al 2014 Scortegagna et al</rights><rights>2014 Scortegagna et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Scortegagna M, Kim H, Li J-L, Yao H, Brill LM, et al. (2014) Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2. 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In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Cells, Cultured</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Enzyme Activation</subject><subject>Experiments</subject><subject>Genetic transcription</subject><subject>Health aspects</subject><subject>Heart attacks</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Ischemia</subject><subject>Isoenzymes - metabolism</subject><subject>Kinases</subject><subject>Ligases</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Protein folding</subject><subject>Protein research</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Regulation</subject><subject>Research and Analysis Methods</subject><subject>RNA, Messenger - genetics</subject><subject>Rodents</subject><subject>Stress response</subject><subject>Stress, Physiological</subject><subject>Transcription factors</subject><subject>Transcription, Genetic</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Unfolded Protein Response</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkl1rFDEUhgdR7If-A9EBQfRit_nOzI1QitWFYqW13oZkksxmmU22k4y0_95sd1p2wAslFzmcPOfNSc5bFG8gmEPM4ckqDL2X3XzTGj-HABBMqmfFIaQUzzgB5PlefFAcxbgCANOq5i-LA0QqUGNCDwt-7rwp0-Cdb8tgy7Q05c2Pq1LdP4SDcreDS86XnWtlNLG8dnIJT9Cr4oWVXTSvx_24uDn_8vPs2-zi8uvi7PRi1rC6SjMoOWmwYlQrCm2DbG0VoEYRiKGmvLJYM2QyQ1nNKlNzzBotKZKKKaWAwsfFu53upgtRjG-OAlLMAEWc8UwsdoQOciU2vVvL_l4E6cRDIvStkH1yTWcE09pCjTSwhhFtaa14zaQBFQMIWYuy1ufxtkGtjW6MT73sJqLTE--Wog2_BQGQEESzwMdRoA-3g4lJrF1sTNdJb8Kw7RthAioEQUbf79BW5tactyErNltcnOIKQ045IZma_4XKS5u1a4I31uX8pODTpCAzydylVg4xisX11X-w3_-dvfw1ZT_ssUsju7SMoRuSCz5OQbIDmz7E2Bv79NUQiK3LHycuti4Xo8tz2dv9MT0VPdoa_wHV7vT6</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Scortegagna, Marzia</creator><creator>Kim, Hyungsoo</creator><creator>Li, Jian-Liang</creator><creator>Yao, Hang</creator><creator>Brill, Laurence M</creator><creator>Han, Jaeseok</creator><creator>Lau, Eric</creator><creator>Bowtell, David</creator><creator>Haddad, Gabriel</creator><creator>Kaufman, Randal J</creator><creator>Ronai, Ze'ev A</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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140501</creationdate><title>Fine tuning of the UPR by the ubiquitin ligases Siah1/2</title><author>Scortegagna, Marzia ; 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Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24809345</pmid><doi>10.1371/journal.pgen.1004348</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Biology and Life Sciences Cells, Cultured CHO Cells Cricetinae Cricetulus Endoplasmic reticulum Endoplasmic Reticulum - metabolism Enzyme Activation Experiments Genetic transcription Health aspects Heart attacks Homeostasis Humans Ischemia Isoenzymes - metabolism Kinases Ligases Medicine and Health Sciences Mice Protein folding Protein research Real-Time Polymerase Chain Reaction Regulation Research and Analysis Methods RNA, Messenger - genetics Rodents Stress response Stress, Physiological Transcription factors Transcription, Genetic Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Unfolded Protein Response |
| title | Fine tuning of the UPR by the ubiquitin ligases Siah1/2 |
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