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 Cθ and phospholipase C-γ1 (PLC-γ1) 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 and PLC-γ1 are also downregulated by DTX1. DTX1 interacted with duanyu1531θ and PLC-γ1 and stimulated the degradation of duanyu1531θ and PLC-γ1. T cell anergy-induced proteolysis of duanyu1531θ was prevented in Dtx1(-/-) T cells, supporting the essential role of DTX1 in duanyu1531θ downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of Proteasome inhibitor did not inhibit DTX1-directed duanyu1531θ degradation, but instead DTX1 directed the relocalization of duanyu1531θ 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 DTX1 prevented 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 duanyu1531θ, whereas DTX1-mediated duanyu1531θ degradation further stabilizes Cbl-b.

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