β-Arrestin 2 regulates toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3β
β-Arrestin 2 regulates toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3β
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DOI：
10.1111/j.1365-2567.2010.03256.x
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发表时间：
2010-08-01
期刊：
影响因子：
6.4
通讯作者：
Yin, Deling
中科院分区：
文献类型：
--
作者：
Li, Hui;Sun, Xiuli;Yin, Deling
P&gT；Toll样受体4(TLR4)是TLR家族的重要成员，具有诱导天然免疫炎症产物的功能。然而，TLR4以一种未知的机制参与多种细胞凋亡事件的研究一直是人们关注的焦点。我们的研究发现，TLR4通过影响糖原合成酶激酶-3β(GSK-3β)通路，在血清剥夺诱导的细胞凋亡范式中促进了凋亡信号的传递。血清剥夺诱导GSK-3β激活，从而导致随后的细胞凋亡。有趣的是，这种凋亡级联反应在TLR4存在时被放大，但被β-arrestin 2大大减弱，β-arrestin 2是TLR4介导的免疫反应中的另一个关键分子。我们的数据表明，β-arrestin 2与GSK-3β的结合有助于磷酸化GSK-3β的稳定，这是GSK-3β的一种非活性形式。总之，我们证明了TLR4具有促进GSK-3β活化从而恶化血清剥夺诱导的细胞凋亡的能力；β-arrestin 2通过控制GSK-3β激活和失活的动态平衡，对TLR4介导的细胞凋亡级联具有抑制作用。
P>Toll-like receptor 4 (TLR4), a key member of the TLR family, has been well characterized by its function in the induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events by an unknown mechanism has been the focus of great interest. Our investigation found that TLR4 promoted apoptotic signalling by affecting the glycogen synthase kinase-3 beta (GSK-3 beta) pathway in a serum-deprivation-induced apoptotic paradigm. Serum deprivation induces GSK-3 beta activation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 but greatly attenuated by beta-arrestin 2, another critical molecule implicated in TLR4-mediated immune responses. Our data suggest that the association of beta-arrestin 2 with GSK-3 beta contributes to the stabilization of phospho-GSK-3 beta, an inactive form of GSK-3 beta. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis by beta-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3 beta activation thereby deteriorating serum-deprivation-induced apoptosis; beta-arrestin 2 represents an inhibitory effect on the TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3 beta.