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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Bibliographic Details
Published in:PLOS Neglected Tropical Diseases
Main Authors: Akira Kawashima, Mitsuo Kiriya, Junichiro En, Kazunari Tanigawa, Yasuhiro Nakamura, Yoko Fujiwara, Yuqian Luo, Keiji Maruyama, Shigekazu Watanabe, Masamichi Goto, Koichi Suzuki
Format: Article in Journal/Newspaper
Language:English
Published: Public Library of Science (PLoS) 2022
Subjects:
Arctic medicine. Tropical medicine
RC955-962
Public aspects of medicine
RA1-1270
Arctic
Online Access:https://doi.org/10.1371/journal.pntd.0010672
https://doaj.org/article/98f67d703dad4e8380167fbe7e647286
Description
Summary: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.

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