Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4
Mycolactone is the exotoxin virulence factor of Mycobacterium ulcerans that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding que...
Gespeichert in:
Veröffentlicht in: | Cell death & disease 2018-03, Vol.9 (3), p.397-15, Article 397 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 15 |
---|---|
container_issue | 3 |
container_start_page | 397 |
container_title | Cell death & disease |
container_volume | 9 |
creator | Ogbechi, Joy Hall, Belinda S. Sbarrato, Thomas Taunton, Jack Willis, Anne E. Wek, Ronald C. Simmonds, Rachel E. |
description | Mycolactone is the exotoxin virulence factor of
Mycobacterium ulcerans
that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation. Validation of these results supports a mechanism by which mycolactone activates an integrated stress response meditated by phosphorylation of eIF2α via multiple kinases (PERK, GCN, PKR) without activation of the ER stress sensors IRE1 or ATF6. The response therefore uncouples the integrated stress response from ER stress, and features translational and transcriptional modes of genes expression that feature the key regulatory transcription factor ATF4. Emphasising the importance of this uncoupled response in cytotoxicity, downstream activation of this pathway is abolished in cells expressing mycolactone-resistant Sec61α variants. Using multiple genetic and biochemical approaches, we demonstrate that eIF2α phosphorylation is responsible for mycolactone-dependent translation attenuation, which initially protects cells from cell death. However, chronic activation without stress remediation enhances autophagy and apoptosis of cells by a pathway facilitated by ATF4 and CHOP. Our findings demonstrate that priming events at the ER can result in the sensing of stress within different cellular compartments. |
doi_str_mv | 10.1038/s41419-018-0427-y |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5852046</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2019478445</sourcerecordid><originalsourceid>FETCH-LOGICAL-c536t-ebd270040ee3ab8a8d3afb2599871d5cb1836b4bf0385c3ef4e478700f18bc043</originalsourceid><addsrcrecordid>eNp1Uctu3CAURVGrJErzAd1ESN3WLRiw8aZSFCVtpEiV2nSNAF_PEHnABTyKP6r_WJKZPLooC0Dc87jcg9B7Sj5RwuTnxCmnXUWorAiv22o5QMc14bTiUnZvXt2P0GlKd6QsxkgtmkN0VHeCk6aVx-jPtV8747ILHocB_wTb0KqHCXwPPuMctU9jsPoRYBa8WWwYtc3BA569DfM0QsJ5Ddj5DKuoM_Q45Qgp4bJNwSfAQwwbfPlj__4R99FtnV9hu-SQw72zLi946_Te7tFMj7jYuK1-au389oq_Q28HPSY43Z8n6NfV5e3Ft-rm-9fri_ObygrW5ApMX7eEcALAtJFa9kwPphZdJ1vaC2uoZI3hZihzFJbBwIG3sjAGKo0lnJ2gLzvdaTYb6G0ZRdSjmqLb6LiooJ36t-LdWq3CVgkpytybIvBhLxDD7xlSVndhjuVTSdWEdsWNc1FQdIeyMaQUYXh2oEQ9hKx2IasSsnoIWS2Fc_a6tWfGU6QFUO8AqZT8CuKL9f9V_wI_xLhz</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2019478445</pqid></control><display><type>article</type><title>Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4</title><source>Nature_OA刊</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><creator>Ogbechi, Joy ; Hall, Belinda S. ; Sbarrato, Thomas ; Taunton, Jack ; Willis, Anne E. ; Wek, Ronald C. ; Simmonds, Rachel E.</creator><creatorcontrib>Ogbechi, Joy ; Hall, Belinda S. ; Sbarrato, Thomas ; Taunton, Jack ; Willis, Anne E. ; Wek, Ronald C. ; Simmonds, Rachel E.</creatorcontrib><description>Mycolactone is the exotoxin virulence factor of
Mycobacterium ulcerans
that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation. Validation of these results supports a mechanism by which mycolactone activates an integrated stress response meditated by phosphorylation of eIF2α via multiple kinases (PERK, GCN, PKR) without activation of the ER stress sensors IRE1 or ATF6. The response therefore uncouples the integrated stress response from ER stress, and features translational and transcriptional modes of genes expression that feature the key regulatory transcription factor ATF4. Emphasising the importance of this uncoupled response in cytotoxicity, downstream activation of this pathway is abolished in cells expressing mycolactone-resistant Sec61α variants. Using multiple genetic and biochemical approaches, we demonstrate that eIF2α phosphorylation is responsible for mycolactone-dependent translation attenuation, which initially protects cells from cell death. However, chronic activation without stress remediation enhances autophagy and apoptosis of cells by a pathway facilitated by ATF4 and CHOP. Our findings demonstrate that priming events at the ER can result in the sensing of stress within different cellular compartments.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-018-0427-y</identifier><identifier>PMID: 29540678</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/109 ; 13/2 ; 14 ; 14/19 ; 38 ; 38/23 ; 38/39 ; 38/70 ; 38/77 ; 42 ; 42/41 ; 45 ; 64 ; 82 ; 82/29 ; 82/80 ; 96 ; Activating transcription factor 4 ; Activating Transcription Factor 4 - genetics ; Activating Transcription Factor 4 - metabolism ; Animals ; Antibodies ; Apoptosis ; Autophagy ; Bacterial Toxins - toxicity ; Biochemistry ; Biomedical and Life Sciences ; Buruli ulcer ; Cell activation ; Cell Biology ; Cell Culture ; Cell death ; Cell Line ; Cellular stress response ; Cytotoxicity ; Endoplasmic reticulum ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - genetics ; Endoplasmic Reticulum - metabolism ; Endoplasmic Reticulum Stress - drug effects ; Eukaryotic Initiation Factor-2 - genetics ; Eukaryotic Initiation Factor-2 - metabolism ; Exotoxins ; Gene expression ; Humans ; Immunology ; Life Sciences ; Macrolides - toxicity ; Mice ; Phagocytosis ; Phosphorylation ; Protein Transport - drug effects ; SEC Translocation Channels - genetics ; SEC Translocation Channels - metabolism ; Signal transduction ; Stress response ; Virulence factors</subject><ispartof>Cell death & disease, 2018-03, Vol.9 (3), p.397-15, Article 397</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-ebd270040ee3ab8a8d3afb2599871d5cb1836b4bf0385c3ef4e478700f18bc043</citedby><cites>FETCH-LOGICAL-c536t-ebd270040ee3ab8a8d3afb2599871d5cb1836b4bf0385c3ef4e478700f18bc043</cites><orcidid>0000-0001-5924-7647 ; 0000-0003-4843-8266</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852046/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852046/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29540678$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ogbechi, Joy</creatorcontrib><creatorcontrib>Hall, Belinda S.</creatorcontrib><creatorcontrib>Sbarrato, Thomas</creatorcontrib><creatorcontrib>Taunton, Jack</creatorcontrib><creatorcontrib>Willis, Anne E.</creatorcontrib><creatorcontrib>Wek, Ronald C.</creatorcontrib><creatorcontrib>Simmonds, Rachel E.</creatorcontrib><title>Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Mycolactone is the exotoxin virulence factor of
Mycobacterium ulcerans
that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation. Validation of these results supports a mechanism by which mycolactone activates an integrated stress response meditated by phosphorylation of eIF2α via multiple kinases (PERK, GCN, PKR) without activation of the ER stress sensors IRE1 or ATF6. The response therefore uncouples the integrated stress response from ER stress, and features translational and transcriptional modes of genes expression that feature the key regulatory transcription factor ATF4. Emphasising the importance of this uncoupled response in cytotoxicity, downstream activation of this pathway is abolished in cells expressing mycolactone-resistant Sec61α variants. Using multiple genetic and biochemical approaches, we demonstrate that eIF2α phosphorylation is responsible for mycolactone-dependent translation attenuation, which initially protects cells from cell death. However, chronic activation without stress remediation enhances autophagy and apoptosis of cells by a pathway facilitated by ATF4 and CHOP. Our findings demonstrate that priming events at the ER can result in the sensing of stress within different cellular compartments.</description><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/2</subject><subject>14</subject><subject>14/19</subject><subject>38</subject><subject>38/23</subject><subject>38/39</subject><subject>38/70</subject><subject>38/77</subject><subject>42</subject><subject>42/41</subject><subject>45</subject><subject>64</subject><subject>82</subject><subject>82/29</subject><subject>82/80</subject><subject>96</subject><subject>Activating transcription factor 4</subject><subject>Activating Transcription Factor 4 - genetics</subject><subject>Activating Transcription Factor 4 - metabolism</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Bacterial Toxins - toxicity</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Buruli ulcer</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell death</subject><subject>Cell Line</subject><subject>Cellular stress response</subject><subject>Cytotoxicity</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - genetics</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Eukaryotic Initiation Factor-2 - genetics</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Exotoxins</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Immunology</subject><subject>Life Sciences</subject><subject>Macrolides - toxicity</subject><subject>Mice</subject><subject>Phagocytosis</subject><subject>Phosphorylation</subject><subject>Protein Transport - drug effects</subject><subject>SEC Translocation Channels - genetics</subject><subject>SEC Translocation Channels - metabolism</subject><subject>Signal transduction</subject><subject>Stress response</subject><subject>Virulence factors</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1Uctu3CAURVGrJErzAd1ESN3WLRiw8aZSFCVtpEiV2nSNAF_PEHnABTyKP6r_WJKZPLooC0Dc87jcg9B7Sj5RwuTnxCmnXUWorAiv22o5QMc14bTiUnZvXt2P0GlKd6QsxkgtmkN0VHeCk6aVx-jPtV8747ILHocB_wTb0KqHCXwPPuMctU9jsPoRYBa8WWwYtc3BA569DfM0QsJ5Ddj5DKuoM_Q45Qgp4bJNwSfAQwwbfPlj__4R99FtnV9hu-SQw72zLi946_Te7tFMj7jYuK1-au389oq_Q28HPSY43Z8n6NfV5e3Ft-rm-9fri_ObygrW5ApMX7eEcALAtJFa9kwPphZdJ1vaC2uoZI3hZihzFJbBwIG3sjAGKo0lnJ2gLzvdaTYb6G0ZRdSjmqLb6LiooJ36t-LdWq3CVgkpytybIvBhLxDD7xlSVndhjuVTSdWEdsWNc1FQdIeyMaQUYXh2oEQ9hKx2IasSsnoIWS2Fc_a6tWfGU6QFUO8AqZT8CuKL9f9V_wI_xLhz</recordid><startdate>20180314</startdate><enddate>20180314</enddate><creator>Ogbechi, Joy</creator><creator>Hall, Belinda S.</creator><creator>Sbarrato, Thomas</creator><creator>Taunton, Jack</creator><creator>Willis, Anne E.</creator><creator>Wek, Ronald C.</creator><creator>Simmonds, Rachel E.</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5924-7647</orcidid><orcidid>https://orcid.org/0000-0003-4843-8266</orcidid></search><sort><creationdate>20180314</creationdate><title>Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4</title><author>Ogbechi, Joy ; Hall, Belinda S. ; Sbarrato, Thomas ; Taunton, Jack ; Willis, Anne E. ; Wek, Ronald C. ; Simmonds, Rachel E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-ebd270040ee3ab8a8d3afb2599871d5cb1836b4bf0385c3ef4e478700f18bc043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/109</topic><topic>13/2</topic><topic>14</topic><topic>14/19</topic><topic>38</topic><topic>38/23</topic><topic>38/39</topic><topic>38/70</topic><topic>38/77</topic><topic>42</topic><topic>42/41</topic><topic>45</topic><topic>64</topic><topic>82</topic><topic>82/29</topic><topic>82/80</topic><topic>96</topic><topic>Activating transcription factor 4</topic><topic>Activating Transcription Factor 4 - genetics</topic><topic>Activating Transcription Factor 4 - metabolism</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Bacterial Toxins - toxicity</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Buruli ulcer</topic><topic>Cell activation</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell death</topic><topic>Cell Line</topic><topic>Cellular stress response</topic><topic>Cytotoxicity</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Endoplasmic Reticulum - genetics</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Eukaryotic Initiation Factor-2 - genetics</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Exotoxins</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Immunology</topic><topic>Life Sciences</topic><topic>Macrolides - toxicity</topic><topic>Mice</topic><topic>Phagocytosis</topic><topic>Phosphorylation</topic><topic>Protein Transport - drug effects</topic><topic>SEC Translocation Channels - genetics</topic><topic>SEC Translocation Channels - metabolism</topic><topic>Signal transduction</topic><topic>Stress response</topic><topic>Virulence factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ogbechi, Joy</creatorcontrib><creatorcontrib>Hall, Belinda S.</creatorcontrib><creatorcontrib>Sbarrato, Thomas</creatorcontrib><creatorcontrib>Taunton, Jack</creatorcontrib><creatorcontrib>Willis, Anne E.</creatorcontrib><creatorcontrib>Wek, Ronald C.</creatorcontrib><creatorcontrib>Simmonds, Rachel E.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ogbechi, Joy</au><au>Hall, Belinda S.</au><au>Sbarrato, Thomas</au><au>Taunton, Jack</au><au>Willis, Anne E.</au><au>Wek, Ronald C.</au><au>Simmonds, Rachel E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2018-03-14</date><risdate>2018</risdate><volume>9</volume><issue>3</issue><spage>397</spage><epage>15</epage><pages>397-15</pages><artnum>397</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Mycolactone is the exotoxin virulence factor of
Mycobacterium ulcerans
that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation. Validation of these results supports a mechanism by which mycolactone activates an integrated stress response meditated by phosphorylation of eIF2α via multiple kinases (PERK, GCN, PKR) without activation of the ER stress sensors IRE1 or ATF6. The response therefore uncouples the integrated stress response from ER stress, and features translational and transcriptional modes of genes expression that feature the key regulatory transcription factor ATF4. Emphasising the importance of this uncoupled response in cytotoxicity, downstream activation of this pathway is abolished in cells expressing mycolactone-resistant Sec61α variants. Using multiple genetic and biochemical approaches, we demonstrate that eIF2α phosphorylation is responsible for mycolactone-dependent translation attenuation, which initially protects cells from cell death. However, chronic activation without stress remediation enhances autophagy and apoptosis of cells by a pathway facilitated by ATF4 and CHOP. Our findings demonstrate that priming events at the ER can result in the sensing of stress within different cellular compartments.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29540678</pmid><doi>10.1038/s41419-018-0427-y</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-5924-7647</orcidid><orcidid>https://orcid.org/0000-0003-4843-8266</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2041-4889 |
ispartof | Cell death & disease, 2018-03, Vol.9 (3), p.397-15, Article 397 |
issn | 2041-4889 2041-4889 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5852046 |
source | Nature_OA刊; MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Directory of Open Access Journals; Springer Nature OA Free Journals |
subjects | 13/1 13/106 13/109 13/2 14 14/19 38 38/23 38/39 38/70 38/77 42 42/41 45 64 82 82/29 82/80 96 Activating transcription factor 4 Activating Transcription Factor 4 - genetics Activating Transcription Factor 4 - metabolism Animals Antibodies Apoptosis Autophagy Bacterial Toxins - toxicity Biochemistry Biomedical and Life Sciences Buruli ulcer Cell activation Cell Biology Cell Culture Cell death Cell Line Cellular stress response Cytotoxicity Endoplasmic reticulum Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - genetics Endoplasmic Reticulum - metabolism Endoplasmic Reticulum Stress - drug effects Eukaryotic Initiation Factor-2 - genetics Eukaryotic Initiation Factor-2 - metabolism Exotoxins Gene expression Humans Immunology Life Sciences Macrolides - toxicity Mice Phagocytosis Phosphorylation Protein Transport - drug effects SEC Translocation Channels - genetics SEC Translocation Channels - metabolism Signal transduction Stress response Virulence factors |
title | Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T09%3A39%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20Sec61-dependent%20translocation%20by%20mycolactone%20uncouples%20the%20integrated%20stress%20response%20from%20ER%20stress,%20driving%20cytotoxicity%20via%20translational%20activation%20of%20ATF4&rft.jtitle=Cell%20death%20&%20disease&rft.au=Ogbechi,%20Joy&rft.date=2018-03-14&rft.volume=9&rft.issue=3&rft.spage=397&rft.epage=15&rft.pages=397-15&rft.artnum=397&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-018-0427-y&rft_dat=%3Cproquest_pubme%3E2019478445%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2019478445&rft_id=info:pmid/29540678&rfr_iscdi=true |