Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.
Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.
复制标题
DOI：
10.1016/j.bcp.2017.09.008
复制
发表时间：
2017-12-15
影响因子：
5.8
通讯作者：
Moniri NH
中科院分区：
文献类型：
--
作者：
Cheshmehkani A;Senatorov IS;Dhuguru J;Ghoneim O;Moniri NH
G蛋白偶联的游离脂肪酸受体4(FFA4)的激动性已被证明在巨噬细胞中促进了由于与β-arrestin伙伴蛋白相互作用而产生的许多抗炎作用。人类在功能上表达不同的短和长FFA4剪接变体，如FFA4-S通过GαQ/11和β-arrestin信号，而Ffa4-L天生只偏向β-arrestin信号。最近，我们和其他人发现，FFA4C末端的磷酸化与β-arrestin的相互作用和信号转导有关。鉴于β-arrestin在β-arrestin抗炎作用中的重要作用，本研究的目的是研究C端arrestin磷酸化传感器在PMA和脂多糖诱导的小鼠Raw 264.7巨噬细胞Ffa4信号转导中的作用。我们的数据首次揭示了两种FFA4亚型都调节了PMA诱导的ROS的产生，而取消FFA4-S，而不是FFA4-L C端磷酸传感器，对这一作用是不利的。此外，我们还发现，虽然这两种异构体都可以降低PMA诱导的COX-2的表达，但移除FFA4-S磷酸传感器显著降低了这种反应，表明FFA4-S的这些作用是由β-arrestin介导的。反之，FFA4-S和缺失β-arrestin磷酸感受器的截短C端同系物均能降低κB活性和ERK1/2的磷酸化水平。然而，Ffa4-L及其相应的突变体都不能调节这些反应，这表明这些反应是由G蛋白偶联介导的。综上所述，我们的数据揭示了两种FFA4亚型之间的重要结构-功能和信号差异，并首次将FFA4与巨噬细胞中ROS的调节联系起来。
Agonism of the G protein-coupled Free-Fatty Acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling. Given the significance of β-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal β-arrestin phosphosensor in FFA4 signaling induced by PMA and LPS in murine Raw 264.7 macrophages. Our data reveal for the first time that both FFA4 isoforms modulate PMA-induced ROS generation, and that abolishment of the FFA4-S, but not FFA4-L C-terminal phosphosensor, is detrimental to this effect. Furthermore, we show that while both isoforms reduce PMA-induced expression of COX-2, removal of the FFA4-S phosphosensor significantly decreases this response, suggesting that these effects of FFA4-S are β-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the β-arrestin phosphosensor were both able to reduce LPS-induced NF-κB activity and ERK1/2 phosphorylation. However, FFA4-L and its corresponding mutant were incapable of modulating either, suggesting that these responses are mediated by G protein coupling. Taken together, our data reveal important structure-function and signaling differences between the two FFA4 isoforms, and for the first time link FFA4 to modulation of ROS in macrophages.
登录
查看更多内容
通过芳烃加成环化级联实现 N-(9-Xanthyl)-4-甲苯磺酰胺的高效合成
影响因子：
2
作者：
Lu, Shan-Shan;Lu, Chong-Dao
通讯作者：
Lu, Chong-Dao
DOI：
10.1016/j.bbrc.2010.05.057
发表时间：
2010-06-11
影响因子：
3.1
作者：
Burns, Rebecca N.;Moniri, Nader H.
通讯作者：
Moniri, Nader H.
影响因子：
3.7
作者：
Palmer CD;Rahman FZ;Sewell GW;Ahmed A;Ashcroft M;Bloom SL;Segal AW;Smith AM
通讯作者：
Smith AM
DOI：
10.1038/nri3071
发表时间：
2011-10-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Li, Xinzhi;Yu, Ying;Funk, Colin D.
通讯作者：
Funk, Colin D.