Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
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DOI：
10.1038/s41467-019-09431-3
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发表时间：
2019-03-29
影响因子：
16.6
通讯作者：
Guarda, Greta
中科院分区：
文献类型：
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作者：
Niogret, Charlene;Miah, S. M. Shahjahan;Guarda, Greta
磷酸酶 Shp-2 由于与 NK 抑制性受体相互作用而参与 NK 细胞的发育和功能，但其在 NK 细胞中的确切作用仍不清楚。在这里，我们使用 NK 谱系中条件性缺乏 Shp-2 的小鼠证明，NK 细胞的发育和反应性基本上不受影响。相反，我们发现 Shp-2 主要用于增强 NK 细胞对 IL-15 和 IL-2 激活的反应。当用高剂量 IL-15 或 IL-2 处理时，Shp-2 缺陷型 NK 细胞的增殖和存活率降低。从机制上讲，Shp-2 缺乏会阻碍急性 IL-15 刺激引起的糖酵解和呼吸速率升高，并导致 ERK 激活的严重缺陷。此外，ERK 和 mTOR 级联的抑制很大程度上复制了在不存在 Shp-2 的情况下观察到的缺陷。总之，我们的数据揭示了 Shp-2 作为桥接急性 IL-15 信号传导与下游代谢爆发和 NK 细胞扩增的分子联系的关键功能。
The phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2. Shp-2-deficient NK cells have reduced proliferation and survival when treated with high dose IL-15 or IL-2. Mechanistically, Shp-2 deficiency hampers acute IL-15 stimulation-induced raise in glycolytic and respiration rates, and causes a dramatic defect in ERK activation. Moreover, inhibition of the ERK and mTOR cascades largely phenocopies the defect observed in the absence of Shp-2. Together, our data reveal a critical function of Shp-2 as a molecular nexus bridging acute IL-15 signaling with downstream metabolic burst and NK cell expansion.