@article{8ac48d22ff8d4117bd8ef2e3fe2ca154,
title = "Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection",
abstract = "Subtilase cytotoxin (SubAB) is an AB5 toxin mainly produced by the locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli (STEC) strain such as O113:H21, yet the contribution of SubAB to STEC infectious disease is unclear. We found that SubAB reduced activation of the STEC O113:H21 infection-induced non-canonical NLRP3 inflammasome and interleukin (IL)-1β and IL-18 production in murine macrophages. Downstream of lipopolysaccharide signaling, SubAB suppressed caspase-11 expression by inhibiting interferon-β/STAT1 signaling, followed by disrupting formation of the NLRP3/caspase-1 assembly. These inhibitions were regulated by PERK/IRE1α-dependent endoplasmic reticulum (ER) stress signaling initiated by cleavage of the host ER chaperone BiP by SubAB. Our murine model of SubAB-producing Citrobacter rodentium demonstrated that SubAB promoted C. rodentium proliferation and worsened symptoms such as intestinal hyperplasia and diarrhea. These findings highlight the inhibitory effect of SubAB on the NLRP3 inflammasome via ER stress, which may be associated with STEC survival and infectious disease pathogenicity in hosts.",
keywords = "Bacteriology, Biochemistry, Microbiology, Protein",
author = "Hiroyasu Tsutsuki and Tianli Zhang and Kinnosuke Yahiro and Katsuhiko Ono and Yukio Fujiwara and Sunao Iyoda and Wei, {Fan Yan} and Kazuaki Monde and Kazuko Seto and Makoto Ohnishi and Hiroyuki Oshiumi and Takaaki Akaike and Tomohiro Sawa",
note = "Funding Information: We thank J. B. Gandy for editing of the manuscript. We acknowledge the expert technical assistance of M. Tokunaga (Department of Cell Pathology, Kumamoto University). This work was supported in part by Grants-in-Aid for Scientific Research [(S), (B), (C) and Challenging Exploratory Research] from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, to H.T. (17K10019, 20K08823), Y.F. (16K09247), T. A. (18H05277, 20K21496) and T.S. (18H02098, 19K22258); a grant from the Japan Society for the Promotion of Science (JSPS) to T.S. and T.Z. (20F20408); a grant from the Japan Science and Technology Agency (JST), CREST (JPMJCR2024), to T.A.; a grant from the Takeda Science Foundation to H.T.; and a grant from the Japan Agency for Medical Research and Development(AMED) to K.Y. and S.I. (18fk0108065j0001, 21fk0108611j0001). H.T. T.S. and T.A. experimental design, cell signaling, biochemistry data analysis, writing the paper; T.Z. F.-Y.W. K.M. H.O. cell biology, ELISA, writing the paper; K.Y. and K.O. molecular biology (preparation of SubABwt and SubABmt constructs), data analysis, editing the paper; K.O. S.I. K.S. and M.O. bacterial studies (preparation of C. rodentium strains, isolation of STEC O113, preparation of subAB-deficient O113), editing the paper; Y.F. and H.T. animal studies, histology data analysis. The authors declare no competing interests. Funding Information: We thank J. B. Gandy for editing of the manuscript. We acknowledge the expert technical assistance of M. Tokunaga (Department of Cell Pathology, Kumamoto University). This work was supported in part by Grants-in-Aid for Scientific Research [(S), (B), (C) and Challenging Exploratory Research] from the Ministry of Education, Culture, Sports, Science and Technology ( MEXT ), Japan, to H.T. ( 17K10019 , 20K08823 ), Y.F. ( 16K09247 ), T. A. ( 18H05277 , 20K21496 ) and T.S. ( 18H02098 , 19K22258 ); a grant from the Japan Society for the Promotion of Science (JSPS) to T.S. and T.Z. ( 20F20408 ); a grant from the Japan Science and Technology Agency ( JST ), CREST ( JPMJCR2024 ), to T.A.; a grant from the Takeda Science Foundation to H.T.; and a grant from the Japan Agency for Medical Research and Development (AMED) to K.Y. and S.I. ( 18fk0108065j0001 , 21fk0108611j0001 ). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "15",
doi = "10.1016/j.isci.2022.104050",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}
