Natural Killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator, which dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 “folded” state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in-vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.

中文翻译：

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PKC-θ 抑制 SHP-1 活性调节 NK 细胞活化阈值和细胞毒性

自然杀伤 (NK) 细胞在免疫中起着至关重要的作用，可以杀死病毒感染的细胞和癌细胞。激活性和抑制性 NK 受体与同源配体结合后启动的信号平衡决定了杀伤或耐受。然而，在异质组织环境中调节健康和恶性细胞快速区分 NK 细胞的分子机制尚不完全清楚。SHP-1 酪氨酸磷酸酶是中央负性 NK 细胞调节剂，它使关键的激活信号蛋白去磷酸化。尽管 SHP-1 介导 NK 细胞抑制的机制已部分阐明，但 SHP-1 自身的调节途径仍不清楚。在这里，我们表明 PKC-θ 在 NK 细胞中 S591 残基上的 SHP-1 磷酸化促进了抑制的 SHP-1“折叠”状态。体内. 该研究揭示了一种通过抑制 SHP-1 活性来维持 NK 细胞活化阈值的分子途径。