Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling.
Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling.
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DOI：
10.4049/jimmunol.1401414
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发表时间：
2015-01-15
期刊：
影响因子：
--
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zhao J;Wei J;Bowser RK;Traister RS;Fan MH;Zhao Y
IL-33 是 IL-1 细胞因子家族中相对较新的成员，在过敏性炎症和急性肺损伤中发挥着至关重要的作用。 ST2L 是 IL-33 的受体，在免疫效应细胞和肺上皮细胞上表达，在引发炎症中发挥着关键作用。我们之前已经表明 ST2L 稳定性受泛素蛋白酶体系统调节，但其上游内化尚未研究。在这里，我们证明糖原合酶激酶 3β (GSK3β) 调节 ST2L 内化和 IL-33 信号传导。 IL-33 治疗诱导 ST2L 内化，抑制或下调 GSK3β 会减弱该效应。发现 GSK3β 在 IL-33 处理下与丝氨酸残基 446 上的 ST2L 相互作用。 GSK3β 结合位点突变体 (ST2LS446A) 和磷酸化位点突变体 (ST2LS442A) 对 IL-33 诱导的 ST2L 内化具有抵抗力。我们还发现 IL-33 激活粘着斑激酶 (FAK)。抑制 FAK 会损害 IL-33 诱导的 GSK3β 激活和 ST2L 内化。此外，抑制 ST2L 内化可增强肺上皮细胞中 IL-33 诱导的细胞因子释放。这些结果表明，FAK/GSK3β 对 ST2L 内化的调节可能是减轻肺部炎症的独特策略。
IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. ST2L, the receptor for IL-33, is expressed on immune effector cells and lung epithelia, and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system, however its upstream internalization has not been studied. Here, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2LS446A) and phosphorylation site mutant (ST2LS442A) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Further, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
4.5
作者：
Macagno JP;Diaz Vera J;Yu Y;MacPherson I;Sandilands E;Palmer R;Norman JC;Frame M;Vidal M
通讯作者：
Vidal M
DOI：
10.4049/jimmunol.1003020
发表时间：
2011-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kouzaki H;Iijima K;Kobayashi T;O'Grady SM;Kita H
通讯作者：
Kita H
影响因子：
6.5
作者：
John, Jobin K.;Paraiso, Kim H. T.;Rebecca, Vito W.;Cantini, Liliana P.;Abel, Ethan V.;Pagano, Nicholas;Meggers, Eric;Mathew, Rahel;Krepler, Clemens;Izumi, Victoria;Fang, Bin;Koomen, John M.;Messina, Jane L.;Herlyn, Meenhard;Smalley, Keiran S. M.
通讯作者：
Smalley, Keiran S. M.
影响因子：
16.6
作者：
通讯作者：
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