NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3β
NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3β
复制标题
DOI：
10.1016/j.cellsig.2015.05.012
复制
发表时间：
2015-09-01
影响因子：
4.8
通讯作者：
Kim, Hun Sik
中科院分区：
文献类型：
--
作者：
Kwon, Hyung-Joon;Kwon, Soon Jae;Kim, Hun Sik
NK细胞的激活由来自属于不同家族的多种激活受体的组合信号触发。已经鉴定了几种NK细胞活化受体，但它们在调节效应子功能中的作用主要是在其个体参与的背景下理解的。因此，对多种NK细胞活化信号广泛涉及的信号通路知之甚少。在这里，我们提供的证据表明，糖原合成酶激酶（GSK）-3 β作为一个负调节多种NK细胞激活信号。使用结合NKG 2D和2B 4并测试不同信号分子的活化模型，我们发现GSK-3通过NKG 2D和2B 4单独或组合的参与在调节丝氨酸残基处经历抑制性磷酸化。这种磷酸化的程度与NK细胞活化的程度密切相关。NK细胞功能，如细胞因子产生和细胞毒性，通过GSK-3 β的敲低或用不同的药理学抑制剂对其进行抑制而持续增强，而GSK-3 α同种型的抑制没有影响。此外，NK细胞功能通过GSK-3 β的催化失活形式的过表达而增强。重要的是，GSM-3 β对NK细胞功能的调节对于通过ITAM和非ITAM途径发出信号的多种活化受体是共同的。因此，我们的研究结果表明，GSK-3 β负调节NK细胞活化，GSK-3 β功能的调节可用于增强NK细胞活化。(C)2015 Elsevier Inc. All rights reserved.
Activation of NK cells is triggered by combined signals from multiple activating receptors that belong to different families. Several NK cell activating receptors have been identified, but their role in the regulation of effector functions is primarily understood in the context of their individual engagement. Therefore, little is known about the signaling pathways broadly implicated by the multiple NK cell activation cues. Here we provide evidence pointing to glycogen synthase kinase (GSK)-3 beta as a negative regulator of multiple NK cell activating signals. Using an activation model that combines NKG2D and 2B4 and tests different signaling molecules, we found that GSK-3 undergoes inhibitory phosphorylation at regulatory serine residues by the engagement of NKG2D and 2B4, either individually or in combination. The extent of such phosphorylation was closely correlated with the degree of NK cell activation. NK cell functions, such as cytokine production and cytotoxicity, were consistently enhanced by the knockdown of GSK-3 beta or its inhibition with different pharmacological inhibitors, whereas inhibition of the GSK-3 alpha isoform had no effect. In addition, NK cell function was augmented by the overexpression of a catalytically inactive form of GSK-3 beta. Importantly, the regulation of NK cell function by GSM-3 beta was common to diverse activating receptors that signal through both ITAM and non-ITAM pathways. Thus, our results suggest that GSK-3 beta negatively regulates NK cell activation and that modulation of GSK-3 beta function could be used to enhance NK cell activation. (C) 2015 Elsevier Inc. All rights reserved.