In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 16, No. 8 ( 2022-8-8), p. e0010672-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0010672
DOI:
10.1371/journal.pntd.0010672.g001
DOI:
10.1371/journal.pntd.0010672.g002
DOI:
10.1371/journal.pntd.0010672.g003
DOI:
10.1371/journal.pntd.0010672.g004
DOI:
10.1371/journal.pntd.0010672.g005
DOI:
10.1371/journal.pntd.0010672.t001
DOI:
10.1371/journal.pntd.0010672.s001
DOI:
10.1371/journal.pntd.0010672.s002
DOI:
10.1371/journal.pntd.0010672.s003
DOI:
10.1371/journal.pntd.0010672.s004
DOI:
10.1371/journal.pntd.0010672.s005
DOI:
10.1371/journal.pntd.0010672.s006
DOI:
10.1371/journal.pntd.0010672.s007
DOI:
10.1371/journal.pntd.0010672.s008
DOI:
10.1371/journal.pntd.0010672.s009
DOI:
10.1371/journal.pntd.0010672.r001
DOI:
10.1371/journal.pntd.0010672.r002
DOI:
10.1371/journal.pntd.0010672.r003
DOI:
10.1371/journal.pntd.0010672.r004
DOI:
10.1371/journal.pntd.0010672.r005
DOI:
10.1371/journal.pntd.0010672.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2429704-5
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