Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

The generation of T cell anergy is associated with upregulation of ubiquitin E3 ligases including Casitas B-lineage lymphoma (Cbl-b), Itch, gene related to anergy in lymphocyte, and deltex1 (DTX1). These E3 ligases attenuate T cell activation by targeting to signaling molecules. For example, Cbl-b and Itch promote the degradation of protein kinase C theta (PKC theta) and phospholipase C-gamma 1 (PLC-gamma 1) in anergic Th1 cells. How these anergy-associated E3 ligases coordinate during T cell anergy remains largely unknown. In the current study, we found that PKC theta and PLC-gamma 1 are also downregulated by DTX1. DTX1 interacted with PKC theta and PLC-gamma 1 and stimulated the degradation of PKC theta and PLC-gamma 1. T cell anergy-induced proteolysis of PKC theta was prevented in Dtx1(-/-) T cells, supporting the essential role of DTX1 in PKC theta downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKC theta. Proteasome inhibitor did not inhibit DTX1-directed PKC theta degradation, but instead DTX1 directed the relocalization of PKC theta into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated the possibility that, through the downregulation of PKC theta, DTX1 prevented PKCu-induced Cbl-b degradation and increased Cbl-b protein stability. Our results suggest the coordination between E3 ligases during T cell anergy; DTX1 acts with Cbl-b to assure a more extensive silencing of PKC theta, whereas DTX1-mediated PKC theta degradation further stabilizes Cbl-b.