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Caspase-mediated cleavage of the exosome subunit PM/Scl-75 during apoptosis

Geurt Schilders1, Reinout Raijmakers1, Kelen CR Malmegrim12, Lieselotte Vande Walle3, Xavier Saelens3, Wilma Vree Egberts1, Walther J van Venrooij1, Peter Vandenabeele3 and Ger JM Pruijn1*

Author Affiliations

1 Department of Biomolecular Chemistry, Nijmegen Center for Molecular Life Sciences, Institute for Molecules and Materials, Radboud University Nijmegen, Geert Grooteplein 26–28, Nijmegen, 6525 GA, The Netherlands

2 Center for Cell-Based Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil

3 Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Ghent University, Technologiepark 927, Ghent, B-9052, Belgium

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Arthritis Research & Therapy 2007, 9:R12  doi:10.1186/ar2119

Published: 5 February 2007


Recent studies have implicated the dying cell as a potential reservoir of modified autoantigens that might initiate and drive systemic autoimmunity in susceptible hosts. A number of subunits of the exosome, a complex of 3'→5' exoribonucleases that functions in a variety of cellular processes, are recognized by the so-called anti-PM/Scl autoantibodies, found predominantly in patients suffering from an overlap syndrome of myositis and scleroderma. Here we show that one of these subunits, PM/Scl-75, is cleaved during apoptosis. PM/Scl-75 cleavage is inhibited by several different caspase inhibitors. The analysis of PM/Scl-75 cleavage by recombinant caspase proteins shows that PM/Scl-75 is efficiently cleaved by caspase-1, to a smaller extent by caspase-8, and relatively inefficiently by caspase-3 and caspase-7. Cleavage of the PM/Scl-75 protein occurs in the C-terminal part of the protein at Asp369 (IILD369↓G), and at least a fraction of the resulting N-terminal fragments of PM/Scl-75 remains associated with the exosome. Finally, the implications of PM/Scl-75 cleavage for exosome function and the generation of anti-PM/Scl-75 autoantibodies are discussed.