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Biochem Biophys Res Commun. 2020 Mar 14. pii: S0006-291X(20)30472-1. doi: 10.1016/j.bbrc.2020.03.008. [Epub ahead of print]

Involvement of protein disulfide isomerase in subtilase cytotoxin-induced cell death in HeLa cells.

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Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.
Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:


Subtilase cytotoxin (SubAB) is a member of bacterial AB5 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 AB5 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 AB5 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 eIF2α 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.


Bacitracin; Bacterial AB(5) toxin; ER stress; Protein disulfide isomerase; Subtilase cytotoxin


Conflict of interest statement

Declaration of competing interest The authors declare to no competing financial interests.

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