Research article

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

Geurt Schilders¹ , Reinout Raijmakers¹ , Kelen CR Malmegrim^1,2 , Lieselotte Vande Walle³ , Xavier Saelens³ , Wilma Vree Egberts¹ , Walther J van Venrooij¹ , Peter Vandenabeele³ and Ger JM Pruijn¹

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

author email corresponding author email

Arthritis Research & Therapy 2007, 9:R12doi:10.1186/ar2119

Published:	5 February 2007

Abstract

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.