Usp9X Is Required for Lymphocyte Activation and Homeostasis through Its Control of ZAP70 Ubiquitination and PKCβ Kinase Activity

Abstract

To achieve a durable adaptive immune response, lymphocytes must undergo clonal expansion and induce a survival program that enables the persistence of Ag-experienced cells and the development of memory. During the priming phase of this response, CD4+ T lymphocytes either remain tolerized or undergo clonal expansion. In this article, we show that Usp9X functions as a positive regulatory switch during T lymphocyte priming through removal of inhibitory monoubiquitination from ZAP70. In the absence of Usp9X, an increased amount of ZAP70 localized to early endosomes consistent with the role of monoubiquitin in endocytic sorting. Usp9X becomes competent to deubiquitinate ZAP70 through TCR-dependent phosphorylation and enhancement of its catalytic activity and association with the LAT signalosome. In B lymphocytes, Usp9X is required for the induction of PKCβ kinase activity after BCR-dependent activation. Accordingly, in Usp9X knockout B cells, there was a significant reduction in phospho-CARMA1 levels that resulted in reduced CARMA1/Bcl-10/MALT-1 complex formation and NF-κB–dependent cell survival. The pleiotropic effect of Usp9X during Ag-receptor signaling highlights its importance for the development of an effective and durable adaptive immune response.