title: Caspase-mediated cleavage of the exosome subunit PM/Scl-75 during apoptosis.
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 [see text] 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.
authors.affiliation: 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. g.schilders@ncmls.ru.nl
authors.forename: Geurt
authors.initials: G
authors.lastname: Schilders
authors.forename: Reinout
authors.initials: R
authors.lastname: Raijmakers
authors.forename: Kelen C R
authors.initials: KC
authors.lastname: Malmegrim
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.forename: Wilma
authors.initials: W
authors.lastname: Vree Egberts
authors.forename: Walther J
authors.initials: WJ
authors.lastname: van Venrooij
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Pruijn
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism*; D063326:Exosome Multienzyme Ribonuclease Complex; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; C077044:EXOSC10 protein, human; D020169:Caspases