Sequential regulation of Lck K63-ubiquitination and autophosphorylation by the E3 ligase UBR2 and the phosphatase DUSP22 in TCR signaling

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B709
Abstract ID: 5352

Presenting Author:
Tse-Hua Tan , Distinguished Investigator at Natl. Hlth. Res. Inst.

Abstract:

Dual-specificity phosphatase 22 (DUSP22, also named JKAP) downregulation in peripheral blood T cells is correlated with human SLE nephritis and T-cell leukemia. DUSP22 also dephosphorylates and inactivates Lck in the turn-off stage of TCR signaling, leading to suppression of autoimmune disease.

We found that DUSP22 dephosphorylated the E3 ligase UBR2, leading to SCF E3 ubiquitin complex-mediated UBR2 ubiquitination and degradation. Remarkably, UBR2 induced Lck K63-linked ubiquitination, leading to subsequent Lck Tyr394 autophosphorylation and activation upon TCR signaling. Thus, DUSP22 also can inactivate Lck indirectly by inducing UBR2 degradation. Moreover, the proinflammatory cytokine induction and inflammatory responses in DUSP22 KO mice was blocked by knocking out UBR2 in DUSP22/UBR2 double KO mice. The UBR2-Lck interaction and Lck Lys63-linked ubiquitination were indeed induced in T cells of human SLE patients. Taken together, DUSP22 dephosphorylates UBR2 and induces its degradation, leading to inactivation of Lck and suppression of inflammation. Overall, our results reveal a novel activation mechanism of Lck by K63-linked ubiquitination in TCR signaling.