Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides.
Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides.
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DOI：
10.1038/s41598-018-31096-z
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发表时间：
2018-08-24
影响因子：
4.6
通讯作者：
Kuroda M
中科院分区：
文献类型：
--
作者：
Kanekura K;Harada Y;Fujimoto M;Yagi T;Hayamizu Y;Nagaoka K;Kuroda M
细胞穿透肽（CPPs），包括富含精氨酸的肽，由于其作为一种新型的细胞内药物递送工具的潜力而引起了广泛的关注。另一方面，疾病相关的富含精氨酸的CPPs，如从C9orf72基因翻译的poly-PR和poly-GR，也能有效地进入神经元细胞并杀死它们。虽然无害的CPPs和有害的聚pr /GR都使用相同的精氨酸残基穿透质膜，但对致病CPPs毒性的决定因素知之甚少。在这里，我们发现poly-PR和poly-GR，而不是其他富含arg的CPPs，通过与RNA的相互作用特异性地分布到核仁。重要的是，c9orf72二肽，而不是其他富含arg的CPPs，引起蛋白质翻译和细胞死亡的抑制。提高细胞外pH值可增强poly-PR的细胞渗透性。（PR）的重复数影响二级结构并决定细胞内传递速率和神经毒性，非穿透性短聚PR肽在细胞内的强制传递导致细胞死亡，提示通过调节细胞外环境抑制富含精氨酸二肽的摄取可能是抗聚PR/ gr介导的神经毒性的药物靶点。
Cell-penetrating peptides (CPPs) including arginine-rich peptides are attracting a lot of attention due to their potential as a novel intracellular drug delivery tool without substantial toxicity. On the other hand, disease-associated arginine-rich CPPs, such as poly-PR and poly-GR translated from C9orf72 gene, also efficiently enter neuronal cells and then kill them. Although both non-harmful CPPs and harmful poly-PR/GR penetrate the plasma membrane using same arginine residues, little is known about the factors which determine the toxicity of the pathogenic CPPs. Here, we show that poly-PR and poly-GR, but not other Arg-rich CPPs, specifically distributed to nucleolus via interaction with RNA. Importantly, C9orf72-dipeptides, but not other Arg-rich CPPs, caused inhibition of protein translation and cell death. Raising extracellular pH enhanced the cell penetration of poly-PR. The repeat number of (PR) affected the secondary structure and determined the intracellular delivery rate and neurotoxicity, and enforced intracellular delivery of non-penetrating short poly-PR peptide caused cell death, suggesting that modulation of extracellular environment to inhibit the uptake of Arg-rich dipeptides might be a drug target against poly-PR/GR-mediated neurotoxicity.
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DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
3.7
作者：
Looi CY;Imanishi M;Takaki S;Sato M;Chiba N;Sasahara Y;Futaki S;Tsuchiya S;Kumaki S
通讯作者：
Kumaki S
影响因子：
4.8
作者：
Li, ZH;Zhao, RJ;Gu, JR
通讯作者：
Gu, JR
影响因子：
3.5
作者：
Kanekura, Kohsuke;Yagi, Takuya;Urano, Fumihiko
通讯作者：
Urano, Fumihiko
影响因子：
5.6
作者：
Kristensen M;Birch D;Mørck Nielsen H
通讯作者：
Mørck Nielsen H