PO.CL05.04 · 临床研究
一种通过Shp2凝聚介导PD-1介导T细胞抑制的相分离机制
A phase-separation mechanism underlying PD-1-mediated T-cell inhibition via Shp2 condensation
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
微簇形成是PD1接合的标志，但其物理基础和功能影响仍不清楚。我们表明配体结合的PD1触发Shp2自身结合和液-液相分离，产生动态凝聚体，其液态性依赖于Shp2的催化活性。破坏Shp2自身结合的突变会削弱PD1微簇并降低抑制性信号。这些发现确定Shp2相分离是PD1通路的一种基本组织机制，将酶活化、底物选择性和高阶组装联系起来以抑制T细胞应答。这项工作揭示了PD1介导免疫调节的一种生物物理机制，对改进检查点阻断治疗具有意义。
查看英文原文 English abstract
Microcluster formation is a hallmark of PD1 engagement, but its physical basis and functional impact have remained unclear. We show that ligand-bound PD1 triggers Shp2 self-association and liquid liquid phase separation, generating dynamic condensates whose liquidity depends on Shp2 catalytic activity. Mutations that disrupt Shp2 self-association weaken PD1 microclusters and reduce inhibitory signaling. These findings identify Shp2 phase separation as a fundamental organizing mechanism of the PD1 pathway, linking enzymatic activation, substrate selectivity, and higher-order assembly to suppress T cell responses. This work reveals a biophysical mechanism of PD1-mediated immune regulation with implications for improving checkpoint blockade therapies.
利益披露 Disclosure
T. Masubuchi, None..
G. Wen, None..
X. Song, None..
H. Shao, None..
E. Hui, None.