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The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response
Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress respon...
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| Published in: | PLoS genetics 2015-09, Vol.11 (9), p.e1005491-e1005491 |
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| creator | Mizuno, Tomoaki Masuda, Yuto Irie, Kenji |
| description | Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly understood. In this study, we characterize Snf1 as a negative regulator of Hog1 MAPK in ER stress response. The snf1 mutant cells showed the ER stress resistant phenotype. In contrast, Snf1-hyperactivated cells were sensitive to ER stress. Activated Hog1 levels were increased by snf1 mutation, although Snf1 hyperactivation interfered with Hog1 activation. Ssk1, a specific activator of MAPKKK functioning upstream of Hog1, was induced by ER stress, and its induction was inhibited in a manner dependent on Snf1 activity. Furthermore, we show that the SSK1 promoter is important not only for Snf1-modulated regulation of Ssk1 expression, but also for Ssk1 function in conferring ER stress tolerance. Our data suggest that Snf1 downregulates ER stress response signal mediated by Hog1 through negatively regulating expression of its specific activator Ssk1 at the transcriptional level. We also find that snf1 mutation upregulates the unfolded protein response (UPR) pathway, whereas Snf1 hyperactivation downregulates the UPR activity. Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway. |
| doi_str_mv | 10.1371/journal.pgen.1005491 |
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Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly understood. In this study, we characterize Snf1 as a negative regulator of Hog1 MAPK in ER stress response. The snf1 mutant cells showed the ER stress resistant phenotype. In contrast, Snf1-hyperactivated cells were sensitive to ER stress. Activated Hog1 levels were increased by snf1 mutation, although Snf1 hyperactivation interfered with Hog1 activation. Ssk1, a specific activator of MAPKKK functioning upstream of Hog1, was induced by ER stress, and its induction was inhibited in a manner dependent on Snf1 activity. Furthermore, we show that the SSK1 promoter is important not only for Snf1-modulated regulation of Ssk1 expression, but also for Ssk1 function in conferring ER stress tolerance. Our data suggest that Snf1 downregulates ER stress response signal mediated by Hog1 through negatively regulating expression of its specific activator Ssk1 at the transcriptional level. We also find that snf1 mutation upregulates the unfolded protein response (UPR) pathway, whereas Snf1 hyperactivation downregulates the UPR activity. Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1005491</identifier><identifier>PMID: 26394309</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Brewer's yeast ; Endoplasmic reticulum ; Endoplasmic Reticulum - genetics ; Endoplasmic Reticulum Stress - genetics ; Gene Expression Regulation, Fungal ; Health aspects ; Kinases ; MAP Kinase Signaling System ; Mitogen-activated protein kinases ; Mitogen-Activated Protein Kinases - biosynthesis ; Mitogen-Activated Protein Kinases - genetics ; Mutation ; Protein folding ; Protein-Serine-Threonine Kinases - genetics ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - biosynthesis ; Saccharomyces cerevisiae Proteins - genetics ; Unfolded Protein Response - genetics ; Yeast</subject><ispartof>PLoS genetics, 2015-09, Vol.11 (9), p.e1005491-e1005491</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Mizuno et al 2015 Mizuno et al</rights><rights>2015 Public Library of Science. 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: AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response. PLoS Genet 11(9): e1005491. doi:10.1371/journal.pgen.1005491</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c808t-398b349c2d797c4d071b669a66f61c1c38e94bdefd47721a6807216be3bed29c3</citedby><cites>FETCH-LOGICAL-c808t-398b349c2d797c4d071b669a66f61c1c38e94bdefd47721a6807216be3bed29c3</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/PMC4578879/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578879/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,730,783,787,888,27936,27937,37025,53804,53806</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26394309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Levin, David E</contributor><creatorcontrib>Mizuno, Tomoaki</creatorcontrib><creatorcontrib>Masuda, Yuto</creatorcontrib><creatorcontrib>Irie, Kenji</creatorcontrib><title>The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly understood. In this study, we characterize Snf1 as a negative regulator of Hog1 MAPK in ER stress response. The snf1 mutant cells showed the ER stress resistant phenotype. In contrast, Snf1-hyperactivated cells were sensitive to ER stress. Activated Hog1 levels were increased by snf1 mutation, although Snf1 hyperactivation interfered with Hog1 activation. Ssk1, a specific activator of MAPKKK functioning upstream of Hog1, was induced by ER stress, and its induction was inhibited in a manner dependent on Snf1 activity. Furthermore, we show that the SSK1 promoter is important not only for Snf1-modulated regulation of Ssk1 expression, but also for Ssk1 function in conferring ER stress tolerance. Our data suggest that Snf1 downregulates ER stress response signal mediated by Hog1 through negatively regulating expression of its specific activator Ssk1 at the transcriptional level. We also find that snf1 mutation upregulates the unfolded protein response (UPR) pathway, whereas Snf1 hyperactivation downregulates the UPR activity. Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway.</description><subject>Brewer's yeast</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum - genetics</subject><subject>Endoplasmic Reticulum Stress - genetics</subject><subject>Gene Expression Regulation, Fungal</subject><subject>Health aspects</subject><subject>Kinases</subject><subject>MAP Kinase Signaling System</subject><subject>Mitogen-activated protein kinases</subject><subject>Mitogen-Activated Protein Kinases - biosynthesis</subject><subject>Mitogen-Activated Protein Kinases - genetics</subject><subject>Mutation</subject><subject>Protein folding</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Saccharomyces cerevisiae - genetics</subject><subject>Saccharomyces cerevisiae Proteins - biosynthesis</subject><subject>Saccharomyces cerevisiae Proteins - genetics</subject><subject>Unfolded Protein Response - genetics</subject><subject>Yeast</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqVk11v0zAUhiMEYmPwDxBEQkIgrcWOHTu5Qaqmwap9Ve3g1nKck8RTGhfbKfTf49JuaiQuQL44lv287zny8Ymi1xiNMeH4073pbSfb8aqGbowRSmmOn0THOE3JiFNEnx7sj6IXzt0jRNIs58-jo4SRnBKUH0f6roF4IZVqpDXLjQIXK7Cw1k5LiCfXs8vTeNFV-DS-gVp6vYZ2E8-h7lvpA-uD-sLUOL6ezC7jmfTNT7mJdRefz-OFt-BcgN3KdA5eRs8q2Tp4tY8n0bcv53dnF6Or26_Ts8nVSGUo8yOSZwWhuUpKnnNFS8RxwVguGasYVliRDHJalFCVlPMES5ahEFgBpIAyyRU5id7ufFetcWL_Sk5gniCWpIwkgZjuiNLIe7GyeintRhipxZ8DY2shrdeqBZHxlGeskBRjQpMsy8syDYUVFBJecbbN9nmfrS-WUCrovJXtwHR40-lG1GYtaDDOeB4MPuwNrPnRg_NiqZ2CtpUdmH5bN-aUU4pIQN_t0FqG0nRXmeCotriYUIJTEr5FGqjxX6iwSlhqZTqodDgfCD4OBIHx8MvXsndOTBfz_2Bv_p29_T5k3x-wDcjWN860vdfh6wxBugOVNc5ZqB6fGiOxnYuHjovtXIj9XATZm8M2PYoeBoH8BrQDBRg</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Mizuno, Tomoaki</creator><creator>Masuda, Yuto</creator><creator>Irie, Kenji</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>20150901</creationdate><title>The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response</title><author>Mizuno, Tomoaki ; Masuda, Yuto ; Irie, Kenji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c808t-398b349c2d797c4d071b669a66f61c1c38e94bdefd47721a6807216be3bed29c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Brewer's yeast</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum - genetics</topic><topic>Endoplasmic Reticulum Stress - genetics</topic><topic>Gene Expression Regulation, Fungal</topic><topic>Health aspects</topic><topic>Kinases</topic><topic>MAP Kinase Signaling System</topic><topic>Mitogen-activated protein kinases</topic><topic>Mitogen-Activated Protein Kinases - biosynthesis</topic><topic>Mitogen-Activated Protein Kinases - genetics</topic><topic>Mutation</topic><topic>Protein folding</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Saccharomyces cerevisiae - genetics</topic><topic>Saccharomyces cerevisiae Proteins - biosynthesis</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Unfolded Protein Response - genetics</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mizuno, Tomoaki</creatorcontrib><creatorcontrib>Masuda, Yuto</creatorcontrib><creatorcontrib>Irie, Kenji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints Resource Center</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mizuno, Tomoaki</au><au>Masuda, Yuto</au><au>Irie, Kenji</au><au>Levin, David E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2015-09-01</date><risdate>2015</risdate><volume>11</volume><issue>9</issue><spage>e1005491</spage><epage>e1005491</epage><pages>e1005491-e1005491</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP-activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly understood. In this study, we characterize Snf1 as a negative regulator of Hog1 MAPK in ER stress response. The snf1 mutant cells showed the ER stress resistant phenotype. In contrast, Snf1-hyperactivated cells were sensitive to ER stress. Activated Hog1 levels were increased by snf1 mutation, although Snf1 hyperactivation interfered with Hog1 activation. Ssk1, a specific activator of MAPKKK functioning upstream of Hog1, was induced by ER stress, and its induction was inhibited in a manner dependent on Snf1 activity. Furthermore, we show that the SSK1 promoter is important not only for Snf1-modulated regulation of Ssk1 expression, but also for Ssk1 function in conferring ER stress tolerance. Our data suggest that Snf1 downregulates ER stress response signal mediated by Hog1 through negatively regulating expression of its specific activator Ssk1 at the transcriptional level. We also find that snf1 mutation upregulates the unfolded protein response (UPR) pathway, whereas Snf1 hyperactivation downregulates the UPR activity. Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26394309</pmid><doi>10.1371/journal.pgen.1005491</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Brewer's yeast Endoplasmic reticulum Endoplasmic Reticulum - genetics Endoplasmic Reticulum Stress - genetics Gene Expression Regulation, Fungal Health aspects Kinases MAP Kinase Signaling System Mitogen-activated protein kinases Mitogen-Activated Protein Kinases - biosynthesis Mitogen-Activated Protein Kinases - genetics Mutation Protein folding Protein-Serine-Threonine Kinases - genetics Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - biosynthesis Saccharomyces cerevisiae Proteins - genetics Unfolded Protein Response - genetics Yeast |
| title | The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response |
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