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Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.

dc.rights.licenseopenen_US
dc.contributor.authorALVAREZ-VALADEZ, Karla
dc.contributor.authorSAUVAT, Allan
dc.contributor.authorDIHARCE, Julien
dc.contributor.authorLEDUC, Marion
dc.contributor.authorSTOLL, Gautier
dc.contributor.authorGUITTAT, Lionel
dc.contributor.authorLAMBERTUCCI, Flavia
dc.contributor.authorPAILLET, Juliette
dc.contributor.authorMOTINO, Omar
dc.contributor.authorFERRET, Lucille
dc.contributor.authorMULLER, Alexandra
dc.contributor.authorFORVEILLE, Sabrina
dc.contributor.authorMAIURI, Maria Chiara
dc.contributor.authorKEPP, Oliver
dc.contributor.authorG DE BREVERN, Alexandre
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorWODRICH, Harald
dc.contributor.authorG POL, Jonathan
dc.contributor.authorKROEMER, Guido
dc.contributor.authorDJAVAHERI-MERGNY, Mojgan
dc.date.accessioned2024-12-13T09:53:24Z
dc.date.available2024-12-13T09:53:24Z
dc.date.issued2024-12-11
dc.identifier.issn1554-8635en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/203922
dc.description.abstractEnCholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.
dc.language.isoENen_US
dc.subjectAutophagy; NPC intracellular cholesterol transporter 1 and 2; TFEB; cancer; lipid transport; lysosomal membrane permeabilization.
dc.title.enLysosomal damage due to cholesterol accumulation triggers immunogenic cell death.
dc.title.alternativeAutophagyen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1080/15548627.2024.2440842en_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologieen_US
dc.identifier.pubmed39663580en_US
bordeaux.journalAutophagyen_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04835667
hal.version1
hal.date.transferred2024-12-13T09:53:26Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Autophagy&rft.date=2024-12-11&rft.eissn=1554-8635&rft.issn=1554-8635&rft.au=ALVAREZ-VALADEZ,%20Karla&SAUVAT,%20Allan&DIHARCE,%20Julien&LEDUC,%20Marion&STOLL,%20Gautier&rft.genre=article


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