Journal
CHEMISTRY & BIOLOGY
Volume 17, Issue 8, Pages 795-801Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2010.05.027
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Funding
- Netherlands Organisation for Scientific Research (NWO)
- Netherlands Genomics Initiative (NGI)
- National Cancer Institute (NCI) [5R01CA124634]
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Epithelial cells of the thymus cortex express a unique proteasome particle involved in positive T cell selection. This thymoproteasome contains the recently discovered beta 5t subunit that has an uncharted activity, if any. We synthesized fluorescent epoxomicin probes that were used in a chemical proteomics approach, entailing activity-based profiling, affinity purification, and LC-MS identification, to demonstrate that the beta 5t subunit is catalytically active in the murine thymus. A panel of established proteasome inhibitors showed that the broad-spectrum inhibitor epoxomicin blocks the beta 5t activity and that the subunit-specific antagonists bortezomib and NC005 do not inhibit beta 5t. We show that beta 5t has a substrate preference distinct from beta 5/beta 5i that might explain how the thymoproteasome generates the MHC class I peptide repertoire needed for positive T cell selection.
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