Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
J Biol Chem. 2013 Aug 23;288(34):24691-704. doi: 10.1074/jbc.M113.469692. Epub 2013 Jul 16.
Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined. In the present study, Humanin increased the mRNA and protein expression of SH3 domain-binding protein 5 (SH3BP5), which has been known to be a JNK interactor, in neuronal cells. Similar to Humanin treatment, overexpression of SH3BP5 inhibited AD-related neuronal death, while siRNA-mediated knockdown of endogenous SH3BP5 expression attenuated the neuroprotective effect of Humanin. These results indicate that SH3BP5 is a downstream effector of Humanin. Furthermore, biochemical analysis has revealed that SH3BP5 binds to JNK and directly inhibits JNK through its two putative mitogen-activated protein kinase interaction motifs (KIMs).
人源素是一种分泌型生物活性肽，可抑制多种损伤引起的细胞毒性。人源素通过与其由睫状神经营养因子受体α、WSX-1 和 gp130 组成的三聚体人源素受体结合，以及激活包括 JAK2 和 STAT3 信号轴在内的细胞内信号通路，对阿尔茨海默病（AD）相关死亡发挥神经保护作用。尽管已经阐明了人源素介导其神经保护作用的信号通路，但作为人源素效应物的人源素的转录靶标仍未确定。在本研究中，人源素增加了神经元细胞中 SH3 结构域结合蛋白 5（SH3BP5）的 mRNA 和蛋白表达，SH3BP5 已知是 JNK 相互作用蛋白。与人源素处理相似，过表达 SH3BP5 抑制 AD 相关的神经元死亡，而 siRNA 介导的内源性 SH3BP5 表达下调则减弱了人源素的神经保护作用。这些结果表明 SH3BP5 是人源素的下游效应物。此外，生化分析表明，SH3BP5 通过其两个假定的丝裂原活化蛋白激酶相互作用基序（KIMs）与 JNK 结合并直接抑制 JNK。
