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Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4

cam.issuedOnline2018-03-14
dc.contributor.authorOgbechi, J
dc.contributor.authorHall, BS
dc.contributor.authorSbarrato, T
dc.contributor.authorTaunton, J
dc.contributor.authorWillis, AE
dc.contributor.authorWek, RC
dc.contributor.authorSimmonds, RE
dc.contributor.orcidWillis, Anne [0000-0002-1470-8531]
dc.date.accessioned2018-07-27T13:28:07Z
dc.date.available2018-07-27T13:28:07Z
dc.date.issued2018-03-14
dc.description.abstractMycolactone 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
dc.description.sponsorshipWellcome Trust
dc.identifier.doi10.17863/CAM.25835
dc.identifier.eissn2041-4889
dc.identifier.issn2041-4889
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/278500
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Nature
dc.publisher.urlhttps://www.nature.com/articles/s41419-018-0427-y#article-info
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectActivating Transcription Factor 4
dc.subjectAnimals
dc.subjectBacterial Toxins
dc.subjectCell Line
dc.subjectEndoplasmic Reticulum
dc.subjectEndoplasmic Reticulum Stress
dc.subjectEukaryotic Initiation Factor-2
dc.subjectHumans
dc.subjectMacrolides
dc.subjectMice
dc.subjectProtein Transport
dc.subjectSEC Translocation Channels
dc.titleInhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4
dc.typeArticle
dcterms.dateAccepted2018-02-13
prism.number397
prism.publicationNameCell Death and Disease
prism.volume9
rioxxterms.licenseref.startdate2018-02-13
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41419-018-0427-y

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