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Infection and Immunity, July 2009, p. 2919-2924, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.01510-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Subtilase Cytotoxin Produced by Shiga-Toxigenic Escherichia coli Induces Apoptosis in Vero Cells via Mitochondrial Membrane Damage{triangledown}

Gen Matsuura,1,2 Naoko Morinaga,1* Kinnosuke Yahiro,1,3 Reiko Komine,1 Joel Moss,3 Hideo Yoshida,2 and Masatoshi Noda1

Departments of Molecular Infectiology,1 Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan,2 Translational Medicine Branch, NHLBI, NIH, Bethesda, Maryland3

Received 11 December 2008/ Returned for modification 19 January 2009/ Accepted 15 April 2009

Subtilase cytotoxin (SubAB) is an AB5 cytotoxin produced by some strains of Shiga-toxigenic Escherichia coli. The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum chaperone, BiP, leading to transient inhibition of protein synthesis and cell cycle arrest at G1 phase. Here we show that SubAB, but not the catalytically inactive mutant SubAB(S272A), induced apoptosis in Vero cells, as detected by DNA fragmentation and annexin V binding. SubAB induced activation of caspase-3, -7, and -8. Caspase-3 appeared earlier than caspase-8, and by use of specific caspase inhibitors, it was determined that caspase-3 may be upstream of caspase-8. A general caspase inhibitor blocked SubAB-induced apoptosis, detected by annexin V binding. SubAB also stimulated cytochrome c release from mitochondria, which was not suppressed by caspase inhibitors. In HeLa cells, Apaf-1 small interfering RNA inhibited caspase-3 activation, suggesting that cytochrome c might form an apoptosome, leading to activation of caspase-3. These data suggested that SubAB induced caspase-dependent apoptosis in Vero cells through mitochondrial membrane damage.

* Corresponding author. Mailing address: 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Phone: (81) 43 226 2048. Fax: (81) 43 226 2049. E-mail: nmorinaga{at}faculty.chiba-u.jp

{triangledown} Published ahead of print on 20 April 2009.

Editor: B. A. McCormick

Infection and Immunity, July 2009, p. 2919-2924, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.01510-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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