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Sprouty2 通过调节 CSK 和 LCK 激酶正向调控 T 细胞功能和气道炎症。

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

机构信息

Division of Allergy and Immunology, Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.

Division of Pulmonary and Critical Care, Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.

出版信息

PLoS Biol. 2021 Mar 8;19(3):e3001063. doi: 10.1371/journal.pbio.3001063. eCollection 2021 Mar.

DOI:10.1371/journal.pbio.3001063
PMID:33684096
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7971865/
Abstract

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

摘要

Sprouty2（Spry2）在 T 细胞中的功能尚不清楚。使用 2 种不同的（诱导型和 T 细胞靶向型）敲除小鼠品系，我们发现 Spry2 通过调节 LCK 的活性正向调节细胞外信号调节激酶 1/2（ERK1/2）信号。Spry2-/- CD4+T 细胞无法激活 LCK、增殖、分化为辅助性 T 细胞或产生细胞因子。Spry2 缺失消除了哮喘小鼠模型中的 2 型炎症和气道高反应性。哮喘患者的血液和气道 CD4+T 细胞中 Spry2 的表达更高，Spry2 敲低会损害人类 T 细胞的增殖和细胞因子产生。Spry2 缺失上调脂筏蛋白窖蛋白-1，增强其与 CSK 的相互作用，并增加 CSK 与 LCK 的相互作用，最终导致 LCK 的抑制性磷酸化增加。CSK 的敲低或窖蛋白-1 结合的 CSK 的位移恢复了 Spry2-/-T 细胞中 ERK1/2 的激活，表明 Spry2 在 LCK 激活和 T 细胞功能中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/5d21fa24d854/pbio.3001063.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/4c5ec927863a/pbio.3001063.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/e54e3a2e5ef4/pbio.3001063.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/1f0378f78872/pbio.3001063.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/7e1ec9735208/pbio.3001063.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/18ecc98d98be/pbio.3001063.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/e65cb7277a1b/pbio.3001063.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/2ed2b1ba4883/pbio.3001063.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/5d21fa24d854/pbio.3001063.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/4c5ec927863a/pbio.3001063.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/e54e3a2e5ef4/pbio.3001063.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/1f0378f78872/pbio.3001063.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/7e1ec9735208/pbio.3001063.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/18ecc98d98be/pbio.3001063.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/e65cb7277a1b/pbio.3001063.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/2ed2b1ba4883/pbio.3001063.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56e5/7971865/5d21fa24d854/pbio.3001063.g008.jpg

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