| First Author | Hsu TS | Year | 2014 |
| Journal | J Immunol | Volume | 193 |
| Issue | 4 | Pages | 1672-80 |
| PubMed ID | 25000980 | Mgi Jnum | J:244855 |
| Mgi Id | MGI:5913634 | Doi | 10.4049/jimmunol.1301416 |
| Citation | Hsu TS, et al. (2014) Deltex1 promotes protein kinase Ctheta degradation and sustains Casitas B-lineage lymphoma expression. J Immunol 193(4):1672-80 |
| abstractText | 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 Ctheta (PKCtheta) and phospholipase C-gamma1 (PLC-gamma1) 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 PKCtheta and PLC-gamma1 are also downregulated by DTX1. DTX1 interacted with PKCtheta and PLC-gamma1 and stimulated the degradation of PKCtheta and PLC-gamma1. T cell anergy-induced proteolysis of PKCtheta was prevented in Dtx1(-/-) T cells, supporting the essential role of DTX1 in PKCtheta downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKCtheta. Proteasome inhibitor did not inhibit DTX1-directed PKCtheta degradation, but instead DTX1 directed the relocalization of PKCtheta 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 PKCtheta, DTX1 prevented PKCtheta-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 PKCtheta, whereas DTX1-mediated PKCtheta degradation further stabilizes Cbl-b. |
