CX3CL1,也被称为fractalkine,最著名的是其通过与其同源受体CX3CR1相互作用的信号活性。然而,其固有功能独立于与CX3CR1的相互作用仍有待充分理解。我们证明CX3CL1的胞内结构域(CX3CL1-ICD),通过α-/β-分泌酶和γ-分泌酶顺序切割产生,启动反向信令活动,介导直接信号传递到细胞核中的基因表达。为了研究这个,我们融合了来自CX3CL1-ICD的合成肽,命名为Tet34,在N末端具有13个氨基酸的破伤风序列,以促进易位到神经元细胞中。我们证明了用Tet34治疗小鼠神经母细胞瘤Neuro-2A细胞,而不是它的加扰对照(Tet34s),诱导细胞增殖,如转录因子和促生长分子cyclinD1,PCNA的蛋白质水平变化所示,Sox5和Cdk2。进一步的生化测定显示磷酸化胰岛素受体β亚基升高,胰岛素样生长因子-1受体β亚基,和胰岛素受体底物以及增殖连接激酶AKT的激活。此外,过表达膜锚定C末端CX3CL1的转基因小鼠也表现出胰岛素/胰岛素样生长因子-1受体信号的激活。值得注意的是,我们发现这个Tet34肽,但不是Tet34s,当Neuro-2A细胞受到β-淀粉样肽或过氧化氢的毒性寡聚体攻击时,可以抵抗内质网应激和细胞凋亡。一起来看,我们的结果提示CX3CL1-ICD可能对阿尔茨海默病和胰岛素抵抗引起的疾病具有神经保护作用.
CX3CL1, also known as fractalkine, is best known for its signaling activity through interactions with its cognate receptor CX3CR1. However, its intrinsic function that is independent of interaction with CX3CR1 remains to be fully understood. We demonstrate that the intracellular domain of CX3CL1 (CX3CL1-ICD), generated upon sequential cleavages by α-/β-secretase and γ-secretase, initiates a back signaling activity, which mediates direct signal transmission to gene expression in the nucleus. To study this, we fused a synthetic peptide derived from CX3CL1-ICD, named Tet34, with a 13-amino acid tetanus sequence at the N terminus to facilitate translocation into neuronal cells. We show that treatment of mouse neuroblastoma Neuro-2A cells with Tet34, but not its scrambled control (Tet34s), induced cell proliferation, as manifested by changes in protein levels of transcription factors and progrowth molecules cyclin D1, PCNA, Sox5, and Cdk2. Further biochemical assays reveal elevation of phosphorylated insulin receptor β subunit, insulin-like growth factor-1 receptor β subunit, and insulin receptor substrates as well as activation of proliferation-linked kinase AKT. In addition, transgenic mice overexpressing membrane-anchored C-terminal CX3CL1 also exhibited activation of insulin/insulin-like growth factor-1 receptor signaling. Remarkably, we found that this Tet34 peptide, but not Tet34s, protected against endoplasmic reticulum stress and cellular apoptosis when Neuro-2A cells were challenged with toxic oligomers of β-amyloid peptide or hydrogen peroxide. Taken together, our results suggest that CX3CL1-ICD may have translational potential for neuroprotection in Alzheimer\'s disease and for disorders resulting from insulin resistance.