抑制还是转导:信号分子调节机体健康与疾病

To arrest or not:a question of health and disease

细胞内的信号转导网络是由多条功能特异且彼此关联的信号通路所构成,它们赋予了细胞功能的多样性和可塑性,同时也必须受到精细严谨的调控。一些功能广泛的信号调节因子,如β-抑制蛋白(β-arrestin),在细胞信号转导网络完整性的维持中扮演着重要的角色。β-arrestin分子的经典功能是终止G-蛋白偶联受体(G-protein-coupled receptors)下游信号转导,即受体脱敏,但最近许多研究证据表明,这种脱敏功能(负调控)还可以针对其他的信号转导途径。例如,β-arrestin能够通过不同的机制负调控三条重要的NF-κB激活通路,该功能异常则导致NF-κB持续激活以及下游炎性因子的过度分泌。此外,近年来发现β-arrestin还能作为支架蛋白介导功能性信号复合物的形成。例如,在特定外界信号刺激下,β-arrestin1能够转移至细胞核内并与组蛋白乙酰化酶p300相互作用而调控基因表达。该机制的生理意义之一反映在多发性硬化症的小鼠模型中,β-arrestin1在发病小鼠中较正常小鼠表达上调并能够显著加重病情。与之相反,在细胞质中富集的β-arrestin2参与了胰岛素激活时InsR/Akt/β-arrestin2/Src信号复合体的形成,它的缺失能够导致胰岛素耐受和2型糖尿病的发生。因此,在特定的条件下,β-arrestin对于胞内信号的传递究竟是抑制还是激活,已成为细胞信号转导中的关键问题,并在机体健康和疾病状态的相互转化中的起着重要作用。

The cellular network of signal transduction comprised of hundreds of distinct but cross-linked pathways that provide diversity and plasticity of cell functions,needs to be delicately regulated.It seems there are a few multifunctional regulators which play important roles in maintaining the integrity of the network,and β-arrestin appears to be one of them.The classical paradigm of β-arrestin function is to arrest the activated G-protein-coupled receptors,but recent evidence indicates that it also desensitizes other signal cascades.For example,our study reveals that β-arrestin tightly regulates all three major NF-κB pathways through different mechanisms,and disruption of this regulation leads to aberrant NF-κB activation and robust up-regulation of inflammatory cytokines.Interestingly,in addition to its well-established negative regulatory functions,β-arrestin aslo facilitates the formation of functional signaling complexes.For instance,β-arrestin1 can locate to the nucleus and complex with the histone acetyltranferase p300 to epigenetically modulate gene expression.Up-regulation of β-arrestin1 expression significantly increases disease severity in a mouse model of multiple sclerosis.By contrast,β-arrestin2 is located abundantly in the cytoplasm,and functionally scaffolds Akt and Src to the activated insulin receptor in mediation of insulin signaling,and its dysfunction contributes to insulin resistance and type II diabetes.Therefore,to arrest or not,as regulated by β-arrestin,is a key question in signal transduction,and could critically determine the status of health and disease.