Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells.
Buruli ulcer is a chronic skin disease caused by a toxic lipid mycolactone produced by Mycobacterium ulcerans, which induces local skin tissue destruction and analgesia. However, the cytotoxicity pathway induced by mycolactone remains largely unknown. Here we investigated the mycolactone-induced cel...
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ftdoajarticles:oai:doaj.org/article:98f67d703dad4e8380167fbe7e647286 2023-05-15T15:07:03+02:00 Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. Akira Kawashima Mitsuo Kiriya Junichiro En Kazunari Tanigawa Yasuhiro Nakamura Yoko Fujiwara Yuqian Luo Keiji Maruyama Shigekazu Watanabe Masamichi Goto Koichi Suzuki 2022-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010672 https://doaj.org/article/98f67d703dad4e8380167fbe7e647286 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010672 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010672 https://doaj.org/article/98f67d703dad4e8380167fbe7e647286 PLoS Neglected Tropical Diseases, Vol 16, Iss 8, p e0010672 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010672 2022-12-31T01:08:41Z Buruli ulcer is a chronic skin disease caused by a toxic lipid mycolactone produced by Mycobacterium ulcerans, which induces local skin tissue destruction and analgesia. However, the cytotoxicity pathway induced by mycolactone remains largely unknown. Here we investigated the mycolactone-induced cell death pathway by screening host factors using a genome-scale lenti-CRISPR mutagenesis assay in human premonocytic THP-1 cells. As a result, 884 genes were identified as candidates causing mycolactone-induced cell death, among which SEC61A1, the α-subunit of the Sec61 translocon complex, was the highest scoring. CRISPR/Cas9 genome editing of SEC61A1 in THP-1 cells suppressed mycolactone-induced endoplasmic reticulum stress, especially eIF2α phosphorylation, and caspase-dependent apoptosis. Although previous studies have reported that mycolactone targets SEC61A1 based on mutation screening and structural analysis in several cell lines, we have reconfirmed that SEC61A1 is a mycolactone target by genome-wide screening in THP-1 cells. These results shed light on the cytotoxicity of mycolactone and suggest that the inhibition of mycolactone activity or SEC61A1 downstream cascades will be a novel therapeutic modality to eliminate the harmful effects of mycolactone in addition to the 8-week antibiotic regimen of rifampicin and clarithromycin. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 8 e0010672 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Akira Kawashima Mitsuo Kiriya Junichiro En Kazunari Tanigawa Yasuhiro Nakamura Yoko Fujiwara Yuqian Luo Keiji Maruyama Shigekazu Watanabe Masamichi Goto Koichi Suzuki Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Buruli ulcer is a chronic skin disease caused by a toxic lipid mycolactone produced by Mycobacterium ulcerans, which induces local skin tissue destruction and analgesia. However, the cytotoxicity pathway induced by mycolactone remains largely unknown. Here we investigated the mycolactone-induced cell death pathway by screening host factors using a genome-scale lenti-CRISPR mutagenesis assay in human premonocytic THP-1 cells. As a result, 884 genes were identified as candidates causing mycolactone-induced cell death, among which SEC61A1, the α-subunit of the Sec61 translocon complex, was the highest scoring. CRISPR/Cas9 genome editing of SEC61A1 in THP-1 cells suppressed mycolactone-induced endoplasmic reticulum stress, especially eIF2α phosphorylation, and caspase-dependent apoptosis. Although previous studies have reported that mycolactone targets SEC61A1 based on mutation screening and structural analysis in several cell lines, we have reconfirmed that SEC61A1 is a mycolactone target by genome-wide screening in THP-1 cells. These results shed light on the cytotoxicity of mycolactone and suggest that the inhibition of mycolactone activity or SEC61A1 downstream cascades will be a novel therapeutic modality to eliminate the harmful effects of mycolactone in addition to the 8-week antibiotic regimen of rifampicin and clarithromycin. |
format |
Article in Journal/Newspaper |
author |
Akira Kawashima Mitsuo Kiriya Junichiro En Kazunari Tanigawa Yasuhiro Nakamura Yoko Fujiwara Yuqian Luo Keiji Maruyama Shigekazu Watanabe Masamichi Goto Koichi Suzuki |
author_facet |
Akira Kawashima Mitsuo Kiriya Junichiro En Kazunari Tanigawa Yasuhiro Nakamura Yoko Fujiwara Yuqian Luo Keiji Maruyama Shigekazu Watanabe Masamichi Goto Koichi Suzuki |
author_sort |
Akira Kawashima |
title |
Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
title_short |
Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
title_full |
Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
title_fullStr |
Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
title_full_unstemmed |
Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. |
title_sort |
genome-wide screening identified sec61a1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic thp-1 cells. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010672 https://doaj.org/article/98f67d703dad4e8380167fbe7e647286 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 8, p e0010672 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010672 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010672 https://doaj.org/article/98f67d703dad4e8380167fbe7e647286 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010672 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
16 |
container_issue |
8 |
container_start_page |
e0010672 |
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1766338629807898624 |