Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 132, Issue 3, Pages 648-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.03.046
Keywords
Wiskott-Aldrich syndrome; Wiskott-Aldrich syndrome protein; T-cell receptor; calpain; ubiquitination; proteasome; F-actin; Cbl family proteins
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Funding
- Japan Ministry of Education, Culture, Sports, Science and Technology
- Japan Ministry of Health, Labour and Welfare
- Japan Foundation for Pediatric Research
- Mother and Child Health Foundation
- US Public Health Service [HL059561]
- National Institutes of Health
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL059561] Funding Source: NIH RePORTER
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Background: Wiskott-Aldrich syndrome protein (WASP) links T-cell receptor (TCR) signaling to the actin cytoskeleton. WASP is normally protected from degradation by the Ca++-dependent protease calpain and by the proteasome because of its interaction with the WASP-interacting protein. Objective: We investigated whether WASP is degraded after TCR ligation and whether its degradation downregulates F-actin assembly caused by TCR ligation. Methods: Primary T cells, Jurkat T cells, and transfected 293T cells were used in immunoprecipitation experiments. Intracellular F-actin content was measured in splenic T cells from wild-type, WASP-deficient, and c-Casitas B-lineage lymphoma (Cbl)-b-deficient mice by using flow cytometry. Calpeptin and MG-132 were used to inhibit calpain and the proteasome, respectively. Results: A fraction of WASP in T cells was degraded by calpain and by the ubiquitin-proteasome pathway after TCR ligation. The Cbl-b and c-Cbl E3 ubiquitin ligases associated with WASP after TCR signaling and caused its ubiquitination. Inhibition of calpain and lack of Cbl-b resulted in a significantly more sustained increase in F-actin content after TCR ligation in wildtype T cells but not in WASP-deficient T cells. Conclusion: TCR ligation causes WASP to be degraded by calpain and to be ubiquitinated by Cbl family E3 ligases, which targets it for destruction by the proteasome. WASP degradation might provide a mechanism for regulating WASP-dependent TCR-driven assembly of F-actin.
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