Mycolactone induces cell death by SETD1B-dependent degradation of glutathione.
Mycobacterium ulcerans is a human pathogen that causes a necrotizing skin disease known as Buruli ulcer. Necrosis of infected skin is driven by bacterial production of mycolactone, a diffusible exotoxin targeting the host translocon (Sec61). By blocking Sec61, mycolactone prevents the transport of n...
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ftdoajarticles:oai:doaj.org/article:267e47cb9db34404abfaf5c1e1f779d0 2023-05-15T15:13:32+02:00 Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. Birgit Förster Caroline Demangel Thorsten Thye 2020-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008709 https://doaj.org/article/267e47cb9db34404abfaf5c1e1f779d0 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008709 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008709 https://doaj.org/article/267e47cb9db34404abfaf5c1e1f779d0 PLoS Neglected Tropical Diseases, Vol 14, Iss 10, p e0008709 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008709 2022-12-31T10:07:30Z Mycobacterium ulcerans is a human pathogen that causes a necrotizing skin disease known as Buruli ulcer. Necrosis of infected skin is driven by bacterial production of mycolactone, a diffusible exotoxin targeting the host translocon (Sec61). By blocking Sec61, mycolactone prevents the transport of nascent secretory proteins into the endoplasmic reticulum of host cells. This triggers pro-apoptotic stress responses partially depending on activation of the ATF4 transcription factor. To gain further insight into the molecular pathways mediating the cytotoxic effects of mycolactone we conducted the first haploid genetic screen with the M. ulcerans toxin in KBM-7 cells. This approach allowed us to identify the histone methyltransferase SETD1B as a novel mediator of mycolactone-induced cell death. CRISPR/Cas9-based inactivation of SETD1B rendered cells resistant to lethal doses of the toxin, highlighting the critical importance of this gene's expression. To understand how SETD1B contributes to mycolactone cytotoxicity, we compared the transcriptomes of wild-type (WT) and SETD1B knockout KBM-7 cells upon exposure to the toxin. While ATF4 effectors were upregulated by mycolactone in both WT and SETD1B knockout cells, mycolactone selectively induced the expression of pro-apoptotic genes in WT cells. Among those genes we identified CHAC1, which codes for a major glutathione (GSH)-degrading enzyme, and whose strong upregulation in mycolactone-treated WT cells correlated with a marked reduction in GSH protein level. Moreover, GSH supplementation conferred cells with substantial protection against the toxic effects of mycolactone. Our data thus identify SETD1B/CHAC1/GSH as a novel, epigenetic mechanism connecting Sec61 blockade with apoptotic cell death. They suggest that GSH-based treatments might have the capacity to limit skin necrosis in Buruli ulcer. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 10 e0008709 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Birgit Förster Caroline Demangel Thorsten Thye Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Mycobacterium ulcerans is a human pathogen that causes a necrotizing skin disease known as Buruli ulcer. Necrosis of infected skin is driven by bacterial production of mycolactone, a diffusible exotoxin targeting the host translocon (Sec61). By blocking Sec61, mycolactone prevents the transport of nascent secretory proteins into the endoplasmic reticulum of host cells. This triggers pro-apoptotic stress responses partially depending on activation of the ATF4 transcription factor. To gain further insight into the molecular pathways mediating the cytotoxic effects of mycolactone we conducted the first haploid genetic screen with the M. ulcerans toxin in KBM-7 cells. This approach allowed us to identify the histone methyltransferase SETD1B as a novel mediator of mycolactone-induced cell death. CRISPR/Cas9-based inactivation of SETD1B rendered cells resistant to lethal doses of the toxin, highlighting the critical importance of this gene's expression. To understand how SETD1B contributes to mycolactone cytotoxicity, we compared the transcriptomes of wild-type (WT) and SETD1B knockout KBM-7 cells upon exposure to the toxin. While ATF4 effectors were upregulated by mycolactone in both WT and SETD1B knockout cells, mycolactone selectively induced the expression of pro-apoptotic genes in WT cells. Among those genes we identified CHAC1, which codes for a major glutathione (GSH)-degrading enzyme, and whose strong upregulation in mycolactone-treated WT cells correlated with a marked reduction in GSH protein level. Moreover, GSH supplementation conferred cells with substantial protection against the toxic effects of mycolactone. Our data thus identify SETD1B/CHAC1/GSH as a novel, epigenetic mechanism connecting Sec61 blockade with apoptotic cell death. They suggest that GSH-based treatments might have the capacity to limit skin necrosis in Buruli ulcer. |
format |
Article in Journal/Newspaper |
author |
Birgit Förster Caroline Demangel Thorsten Thye |
author_facet |
Birgit Förster Caroline Demangel Thorsten Thye |
author_sort |
Birgit Förster |
title |
Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
title_short |
Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
title_full |
Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
title_fullStr |
Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
title_full_unstemmed |
Mycolactone induces cell death by SETD1B-dependent degradation of glutathione. |
title_sort |
mycolactone induces cell death by setd1b-dependent degradation of glutathione. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008709 https://doaj.org/article/267e47cb9db34404abfaf5c1e1f779d0 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 10, p e0008709 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008709 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008709 https://doaj.org/article/267e47cb9db34404abfaf5c1e1f779d0 |
op_doi |
https://doi.org/10.1371/journal.pntd.0008709 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
10 |
container_start_page |
e0008709 |
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1766344075325210624 |