Study on the Molecular Mechanism of Deltex1 in T cell Anergy
| Autor: | Tzu-Sheng Hsu, 徐子勝 |
|---|---|
| Rok vydání: | 2014 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 103 Ubiquitin E3 ligases are associated with induction and maintance of T cell anergy. These E3 ligases, including Cbl-b, Itch, and GRAIL, attenuate T cell activation by targeting to signaling molecules such as PKCθ and PLCγ1 for degradetion. How these anergy-associated E3 ligases coordinate during T cell anergy remains incompletely understood. In this study, we found that Notch-related E3 ligase deltex1 (DTX1) also regulated the expression of PKCθ and PLCγ1. DTX1 interacted with PKCθ and PLCγ1 and promoted the degradation of PKCθ and PLCγ1. T cell anergy-induced downregulation of PKCθ was prevented in Dtx1-/- T cells, supporting the essential role of DTX1 in PKCθ downregulation. DTX1 promoted monoubiquitination of PKCθ, similar to Cbl-b and Itch. DTX1-directed PKCθ degradation was not prevented by proteasome inhibitor, but instead DTX1 directed the re-localization of PKCθ into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated that, through the downregulation of PKCθ, DTX1 prevented PKCθ-induced Cbl-b degradation and increased Cbl-b protein stability. Our results illustrate the coordination between E3 ligases during T cell anergy; DTX1-mediated PKCθ degradation further stabilizes Cbl-b and DTX1 acts with Cbl-b to assure a more completely silencing of PKCθ. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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