| First Author | Ko JS | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 35 | PubMed ID | 34452999 |
| Mgi Jnum | J:309525 | Mgi Id | MGI:6758708 |
| Doi | 10.1073/pnas.2102374118 | Citation | Ko JS, et al. (2021) Ssu72 phosphatase directly binds to ZAP-70, thereby providing fine-tuning of TCR signaling and preventing spontaneous inflammation. Proc Natl Acad Sci U S A 118(35):e2102374118 |
| abstractText | ZAP-70 is required for the initiation of T cell receptor (TCR) signaling, and Ssu72 is a phosphatase that regulates RNA polymerase II activity in the nucleus. However, the mechanism by which ZAP-70 regulates the fine-tuning of TCR signaling remains elusive. Here, we found that Ssu72 contributed to the fine-tuning of TCR signaling by acting as tyrosine phosphatase for ZAP-70. Affinity purification-mass spectrometry and an in vitro assay demonstrated specific interaction between Ssu72 and ZAP-70 in T cells. Upon TCR stimulation, Ssu72-deficient T cells increased the phosphorylation of ZAP-70 and downstream molecules and exhibited hyperresponsiveness, which was restored by reducing ZAP-70 phosphorylation. In vitro assay demonstrated that recombinant Ssu72 reduced tyrosine phosphorylation of ZAP-70 via phosphatase activity. Cd4-CreSsu72 (fl/fl) mice showed a defect in the thymic development of invariant natural killer T cells and reductions in CD4(+) and CD8(+) T cell numbers in the periphery but more CD44(hi)CD62L(lo) memory T cells and fewer CD44(lo)CD62L(hi) naive T cells, compared with wild-type mice. Furthermore, Cd4-CreSsu72 (fl/fl) mice developed spontaneous inflammation at 6 mo. In conclusion, Ssu72 phosphatase regulates the fine-tuning of TCR signaling by binding to ZAP-70 and regulating its tyrosine phosphorylation, thereby preventing spontaneous inflammation. |
