The CX3CL1 intracellular domain exhibits neuroprotection via insulin receptor/insulin-like growth factor receptor signaling.
The CX3CL1 intracellular domain exhibits neuroprotection via insulin receptor/insulin-like growth factor receptor signaling.
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DOI：
10.1016/j.jbc.2022.102532
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发表时间：
2022-11
影响因子：
4.8
通讯作者：
Yan, Riqiang
中科院分区：
文献类型：
--
作者：
Gayen, Manoshi;Benoit, Marc R.;Fan, Qingyuan;Hudobenko, Jacob;Yan, Riqiang
CX 3CL 1，也称为fractalkine，最为人所知的是通过与其同源受体CX 3CR 1相互作用的信号传导活性。然而，其与CX 3CR 1相互作用无关的内在功能仍有待充分理解。我们证明，在α-/β-分泌酶和γ-分泌酶连续切割后产生的CX 3CL 1的细胞内结构域（CX 3CL 1-ICD）启动反向信号传导活性，其介导直接信号传导到核中的基因表达。为了研究这一点，我们融合了一个合成肽CX 3CL 1-ICD，命名为Tet 34，在N端的13个氨基酸的破伤风序列，以促进易位到神经元细胞。我们发现，治疗小鼠神经母细胞瘤Neuro-2A细胞与Tet 34，但不是其乱控制（Tet 34 s），诱导细胞增殖，表现为转录因子和促生长分子细胞周期蛋白D1，PCNA，Sox 5和Cdk 2的蛋白水平的变化。进一步的生物化学测定显示磷酸化胰岛素受体β亚基、胰岛素样生长因子-1受体β亚基和胰岛素受体底物升高以及增殖相关激酶AKT活化。此外，过表达膜锚定的C-末端CX 3CL 1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，这种Tet 34肽，而不是Tet 34 s，保护内质网应激和细胞凋亡时，神经元-2A细胞受到攻击的毒性寡聚体的β-淀粉样蛋白肽或过氧化氢。综上所述，我们的研究结果表明，CX 3CL 1-ICD可能具有翻译的潜力，在阿尔茨海默病和胰岛素抵抗引起的疾病的神经保护。
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.
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影响因子：
5.2
作者：
Lei, Hong;Quelle, Frederick W.
通讯作者：
Quelle, Frederick W.
DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
8.8
作者：
Kennedy LM;Pham SC;Grishok A
通讯作者：
Grishok A
影响因子：
25
作者：
Fu H;Hardy J;Duff KE
通讯作者：
Duff KE
影响因子：
15.1
作者：
Iatrou A;Clark EM;Wang Y
通讯作者：
Wang Y