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

Geurt Schilders1, Reinout Raijmakers, Kelen C R Malmegrim

  • 1Department 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

Arthritis Research & Therapy
|February 7, 2007
PubMed

Insights

Dying cells release modified autoantigens, potentially causing autoimmunity. Researchers found that the exosome subunit PM/Scl-75 is cleaved during apoptosis by caspases, impacting autoimmunity.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Dying cells can harbor modified autoantigens, initiating autoimmunity in susceptible individuals.
  • Anti-PM/Scl autoantibodies target exosome subunits and are prevalent in myositis and scleroderma overlap syndrome.

Purpose of the Study:

  • To investigate the cleavage of the exosome subunit PM/Scl-75 during apoptosis.
  • To determine the role of caspases in PM/Scl-75 cleavage and its implications for autoimmunity.

Main Methods:

  • Studied apoptosis-induced cleavage of PM/Scl-75.
  • Utilized caspase inhibitors and recombinant caspase proteins (caspase-1, -8, -3, -7) to analyze cleavage sites and efficiency.
  • Examined the association of PM/Scl-75 fragments with the exosome.

Main Results:

  • PM/Scl-75 is cleaved during apoptosis, a process inhibited by caspase inhibitors.
  • Caspase-1 and caspase-8 are the primary caspases responsible for PM/Scl-75 cleavage.
  • Cleavage occurs at Asp369, generating N-terminal fragments that remain associated with the exosome.

Conclusions:

  • Apoptotic cleavage of PM/Scl-75 by specific caspases may contribute to the generation of anti-PM/Scl autoantibodies.
  • This cleavage could impact exosome function and play a role in the pathogenesis of systemic autoimmune diseases.

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