Subab—A Specifically Deadly Toxin

RESEARCH HIGHLIGHTS TOXINS SubAB — a specifically deadly toxin The armaments of many bacterial one million. These toxins share a no cleavage of BiP when mice were pathogens include toxins, which similar arrangement of subunits, with challenged with the mutant form of Disrupting often contribute significantly to the a B subunit that forms a pentamer SubAB lacking serine protease activ- this crucially pathology associated with infection. that facilitates uptake into susceptible ity, showing that the toxin is physi- important Adrienne Paton and colleagues now cells, and an enzymatic A subunit ologically functional. Using purified chaperone is report that the subtilase cytotoxin that disables key cell functions. SubAB, Paton et al. revealed that (SubAB), a recently discovered potent In 2004 the Paton group identi- unlike other subtilisin-like enzymes inevitably fatal for AB5 toxin, kills eukaryotic cells by fied the plasmid-borne SubAB this toxin is exquisitely specific, and eukaryotic cells. cleaving the essential endoplasmic toxin, which is produced by a Shiga only cleaves BiP, leaving even related reticulum (ER) chaperone BiP — a toxigenic Escherichia coli O113:H21 proteins intact. They also pinpointed new way to trigger cell death. strain 98NK2 that causes haemolytic the cleavage site in BiP using purified The AB5 toxin family includes uraemic syndrome in humans. proteins. Shiga toxin, which was named after SubAB is the prototype member Inspection of the crystal structure Kiyoshi Shiga, who identified Shigella of a new class of AB5 toxins, and of SubA localized the trio of amino dysenteriae as the causative agent of has a serine protease activity that acids necessary for the serine pro- dysentery in 1897. This family also is essential for cytotoxicity. Paton tease activity inside a deep cleft that includes the pertussis toxin and the and co-workers used a proteomics is partly occluded by protein loops, cholera toxin. Annual deaths result- approach to search for SubAB targets. thereby accounting for the precise ing from infection with AB5 toxin- After challenging cells with either substrate specificity of SubA. Finally, producing bacteria total more than functional SubAB or a mutant that Paton and co-workers engineered a lacked serine protease activity, they toxin-resistant BiP mutant that was looked for proteins that were specifi- able to protect cells from SubAB, cally cleaved by functional toxin. The proving that BiP is the physiological only SubAB target identified was BiP, target of the toxin and that the effects an ER chaperone. Among other func- of SubAB on BiP directly contribute tions, BiP ensures correct folding of to the pathology of toxin-producing secretory proteins, targets misfolded bacterial infection. proteins to the proteasome, is the SubAB is the first toxin identi- ER master regulator of the unfolded fied that targets a chaperone, so protein response and, through this research will be a boon to cell opposing the functions of caspase, biologists interested in diseases that can modulate apoptosis. Disrupting are thought to be related to the mal- this crucially important chaperone is function of ER chaperones, including inevitably fatal for eukaryotic cells. Parkinson’s and Alzheimer’s disease. Cartoon representation of SubA viewing from the S′ end of the active site. The Co-localization studies revealed Susan Jones catalytic triad is in magenta stick and the position of a modelled substrate is shown in yellow stick. Highlighted in red are the 234–239 loop and the N terminus of the that SubAB and BiP are both found ORIGINAL RESEARCH PAPER Paton, A.W. et al. helix flanking the active site (81–88). The elements of the secondary structure lining in the ER lumen. Importantly, SubAB AB subtilase cytotoxin inactivates the ′ 5 the channel leading out of the S side of the active site are highlighted in dark blue cleaved BiP in mouse livers after endoplasmic reticulum chaperone BiP. Nature (119–123 and 152–156). Reproduced with permission from Nature 5 Oct 2006 5 Oct 2006 (doi: 10/1038/nature05124) (doi: 10/1038/nature05124) © (2006) Macmillan Publishers Ltd. injection with the purified toxin, with RESEARCH HIGHLIGHTS ADVISORS ADRIANO AGUZZI University RITA COLWELL KEITH GULL BERNARD MOSS PHILIPPE SANSONETTI Hospital of Zürich, Zürich, Switzerland University of Maryland Biotechnology University of Oxford, Oxford, UK NIAID, National Institutes of Health, Institut Pasteur, Paris, France NORMA ANDREWS Institute, Baltimore, MD, USA NEIL GOW Bethesda, MD, USA CHIHIRO SASAKAWA Yale University School of Medicine, STANLEY FALKOW University of Aberdeen, JOHN REX University of Tokyo, Tokyo, Japan New Haven, CT, USA Stanford University School of Aberdeen, UK AstraZeneca, Cheshire, UK ROBIN WEISS ARTURO CASADEVALL Medicine, Stanford, CA, USA HANS-DIETER KLENK DAVID ROOS University College London, The Albert Einstein College of TIMOTHY FOSTER Philipps University, Marburg, University of Pennsylvania, London, UK Medicine, Bronx, NY, USA Trinity College, Dublin, Ireland Germany Philadelphia, PA, USA NATURE REVIEWS | MICROBIOLOGY VOLUME 4 | NOVEMBER 2006 | 801 © 2006 Nature Publishing Group .

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