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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<jats:italic>SEC61A1<\/jats:italic>, the \u03b1-subunit of the Sec61 translocon complex, was the highest scoring. CRISPR\/Cas9 genome editing of<jats:italic>SEC61A1<\/jats:italic>in THP-1 cells suppressed mycolactone-induced endoplasmic reticulum stress, especially eIF2\u03b1 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.<\/jats:p>","DOI":"10.1371\/journal.pntd.0010672","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T17:36:26Z","timestamp":1659980186000},"page":"e0010672","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 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