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Sci. Signal., 23 June 2009
Vol. 2, Issue 76, p. ra30
[DOI: 10.1126/scisignal.2000046]


PKC-{theta} Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation

Thomas Gruber1, Natascha Hermann-Kleiter1, Reinhard Hinterleitner1, Friedrich Fresser1, Rainer Schneider2, Günther Gastl3, Josef M. Penninger4, and Gottfried Baier1*

1 Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
2 Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
3 Laboratory of Tumor Immunology, Department of Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.

Abstract: The E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl-b) is central to antigen-induced immune tolerance and regulates the CD28 dependence of T cell activation. Cbl-b undergoes ubiquitination and proteasomal degradation after adequate costimulation of T cells; however, the mechanism involved is unknown. Here, we identified protein kinase C-{theta} (PKC-{theta}) as the critical intermediary for the inactivation of Cbl-b in response to costimulation of T cells through CD28. PKC-{theta} associated with Cbl-b on stimulation of the T cell receptor. After costimulation of T cells through CD28, Cbl-b was ubiquitinated and degraded through a mechanism that depended on the kinase activity of PKC-{theta}. Consistent with this mechanism, the impaired responses of PKC{theta}-deficient T cells were at least partially restored by the concomitant genetic loss of cblb. Thus, our data establish a nonredundant antagonism between PKC-{theta} and Cbl-b that regulates T cell activation responses.

* To whom correspondence should be addressed. E-mail: gottfried.baier{at}

Citation: T. Gruber, N. Hermann-Kleiter, R. Hinterleitner, F. Fresser, R. Schneider, G. Gastl, J. M. Penninger, G. Baier, PKC-{theta} Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation. Sci. Signal. 2, ra30 (2009).

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