Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 525, Issue 4, Pages 1068-1073Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2020.03.008
Keywords
Subtilase cytotoxin; Bacterial AB(5) toxin; ER stress; Protein disulfide isomerase; Bacitracin
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Funding
- Ministry of Education, Science, Sports, and Technology (MEXT), Japan [17K10019, 19K22258]
- Takeda Science Foundation
- Japan Science and Technology Agency (JST), Core Research for Evolutionary Science and Technology (CREST) [JPMJCR18H5]
- Grants-in-Aid for Scientific Research [19K22258, 17K10019] Funding Source: KAKEN
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Subtilase cytotoxin (SubAB) is a member of bacterial AB(5) toxin produced by certain enterohemorrhagic E. coli strains which cleaves host chaperone BiP in endoplasmic reticulum (ER), leading to ER stress-mediated cytotoxicity. Previous study suggested that protein disulfide isomerase ( PDI), an enzyme which catalyzes the formation and breakage of disulfide bonds in proteins, regulates AB(5) toxin such as cholera toxin by unfolding of A subunit, leading to its translocation into cytosol to induce disease. Although SubAB targets ER and has similar A subunit to that of other AB(5) toxins, it is unclear whether PDI can modulate the SubAB function. Here we determined the role of PDI on SubAB-induced BiP cleavage, ER stress response and cytotoxicity in HeLa cells. We found that PDI knockdown significantly suppressed SubAB-induced BiP cleavage and eIF2 alpha phosphorylation. The accumulation of SubAB in ER was perturbed upon PDI knockdown. Finally, cell viability assay showed that PDI knockdown and PDI inhibitor canceled the SubAB-induced cytotoxicity. Present results suggested that SubAB, after cellular uptake, translocates into ER and interacts with BiP that might be modulated by PDI. Identification of pivotal role of host proteins on bacterial toxin to elicit its pathogenesis is necessary basis for development of potential chemotherapy and new diagnostic strategy for control of toxin-producing bacterial infections. (C) 2020 Elsevier Inc. All rights reserved.
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