Activity-Based Profiling Reveals Reactivity of the Murine Thymoproteasome-Specific Subunit β5t

被引：68

作者：

Florea, Bogdan I. ^{[1
,2
]}

Verdoes, Martijn ^{[1
,2
]}

Li, Nan ^{[1
,2
]}

van der Linden, Wouter A. ^{[1
,2
]}

Geurink, Paul P. ^{[1
,2
]}

van den Elst, Hans ^{[1
,2
]}

Hofmann, Tanja ^{[1
,2
]}

de Ru, Arnoud ^{[3
]}

van Veelen, Peter A. ^{[3
]}

Tanaka, Keiji ^{[4
]}

Sasaki, Katsuhiro ^{[4
]}

Murata, Shigeo ^{[5
]}

den Dulk, Hans ^{[1
,2
]}

Brouwer, Jaap ^{[1
,2
]}

Ossendorp, Ferry A. ^{[3
]}

Kisselev, Alexei F. ^{[6
]}

Overkleeft, Herman S. ^{[1
,2
]}

机构：

[1] Gorlaeus Labs, Leiden Inst Chem, NL-2333 CC Leiden, Netherlands

[2] Gorlaeus Labs, Netherlands Prote Ctr, NL-2333 CC Leiden, Netherlands

[3] Leiden Univ, Dept Immunohematol & Blood Transfus, Med Ctr, NL-2300 RC Leiden, Netherlands

[4] Tokyo Metropolitan Inst Med Sci, Lab Frontier Sci, Tokyo 1138613, Japan

[5] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Prot Metab, Tokyo 1130033, Japan

[6] Dartmouth Med Sch, Norris Cotton Canc Ctr, Dept Pharmacol & Toxicol, Lebanon, NH 03756 USA

来源：

CHEMISTRY & BIOLOGY | 2010年 / 17卷 / 08期

关键词：

T-CELL REPERTOIRE; PROTEASOME; INHIBITORS; PEPTIDES; PROTEIN; THREONINE; POTENT;

D O I：

10.1016/j.chembiol.2010.05.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：795 / 801

页数：7

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