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Notch signaling protects CD4 T cells from STING-mediated apoptosis during acute systemic inflammation.
Science Advances ( IF 11.7 ) Pub Date : 2020-09-23 , DOI: 10.1126/sciadv.abc5447
Junke Long 1, 2 , Chenxuan Yang 3, 4 , Yawen Zheng 2, 5 , Patricia Loughran 6, 7 , Fu Guang 2, 8 , Yiming Li 9, 10 , Hong Liao 6 , Melanie J Scott 6 , Daolin Tang 11 , Timothy R Billiar 6 , Meihong Deng 6
Affiliation  

Dysregulation of T cell apoptosis contributes to the pathogenesis of acute systemic inflammation–induced immunosuppression, as seen in sepsis and trauma. However, the regulatory mechanisms of T cell apoptosis are unclear. Activation of stimulator of interferon genes (STING) has been shown to induce T cell apoptosis. Notch was previously identified as the top negative regulator of STING in macrophages through a kinase inhibitor library screening. However, how Notch signaling regulates STING activation in T cells is unknown. Here, using a γ-secretase inhibitor to block Notch signaling, we found that Notch protected CD4 T cells from STING-mediated apoptosis during endotoxemia. Mechanistically, Notch intracellular domain (NICD) interacted with STING at the cyclic dinucleotide (CDN) binding domain and competed with CDN to inhibit STING activation. In conclusion, our data reveal a previously unidentified role of Notch in negative regulation of STING-mediated apoptosis in CD4 T cells.



中文翻译:

Notch 信号在急性全身炎症期间保护 CD4 T 细胞免受 STING 介导的细胞凋亡。

如败血症和创伤中所见,T 细胞凋亡的失调有助于急性全身炎症诱导的免疫抑制的发病机制。然而,T细胞凋亡的调控机制尚不清楚。已显示干扰素基因刺激物 (STING) 的激活可诱导 T 细胞凋亡。Notch 之前通过激酶抑制剂库筛选被确定为巨噬细胞中 STING 的最高负调节因子。然而,Notch 信号如何调节 T 细胞中的 STING 激活尚不清楚。在这里,使用 γ-分泌酶抑制剂来阻断 Notch 信号传导,我们发现 Notch 在内毒素血症期间保护 CD4 T 细胞免受 STING 介导的细胞凋亡。从机制上讲,Notch 胞内结构域 (NICD) 在环状二核苷酸 (CDN) 结合结构域与 STING 相互作用,并与 CDN 竞争抑制 STING 激活。

更新日期:2020-09-24
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