The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6.
The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6.
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DOI：
10.1038/nature19312
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发表时间：
2016-08-25
期刊：
影响因子：
64.8
通讯作者：
Aguzzi A
中科院分区：
文献类型：
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作者：
Küffer A;Lakkaraju AK;Mogha A;Petersen SC;Airich K;Doucerain C;Marpakwar R;Bakirci P;Senatore A;Monnard A;Schiavi C;Nuvolone M;Grosshans B;Hornemann S;Bassilana F;Monk KR;Aguzzi A
细胞内PrPC蛋白的消融导致影响雪旺细胞的慢性脱髓鞘多神经病(CDP)。神经元限制性PrPC的表达可以预防这种疾病，这表明它通过一种未知的雪旺细胞受体起反式作用。我们发现PrPC缺陷的坐骨神经中cAMP浓度降低，提示G蛋白偶联受体(GPCR)参与其中。PrPC的氨基末端“柔性尾”(FT，残基23-120)在原代雪旺细胞、雪旺细胞系SW10和过表达GPCRGPR126/Adgrg6的Hek293T细胞中引发cAMP浓度依赖性增加。相反，单纯的HEK293T细胞和表达其他几种GPCRs的HEK293T细胞对FT没有反应，而去除SW10细胞的GPR126则取消了FT诱导的cAMP反应。FT含有一个多阳离子簇(KKRPKPG)，类似于GPR126激动剂IV型胶原(COL4)的GPRGKPG基序。含有KKRPKPG的PrPC衍生肽(FT23-50)足以在细胞和小鼠中诱导依赖GPR126的cAMP反应，并促进低形态GPR126斑马鱼突变体的髓鞘形成。阳离子残基被丙氨酸取代后，FT23-50和相应的COL4多肽都失去了生物活性。我们的结论是PrPC通过FT介导的GPR126激动剂促进髓鞘动态平衡。除了阐明PrPC的生理作用外，这些观察还与脱髓鞘多神经病的发病机制有关，这些疾病是常见的衰弱疾病，治疗选择有限。
Ablation of the cellular prion protein PrPC leads to a chronic demyelinating polyneuropathy (CDP) affecting Schwann cells. Neuron-restricted PrPC expression prevents the disease, suggesting that it acts in trans through an unidentified Schwann cell receptor. We found that the cAMP concentration in PrPC-deficient sciatic nerves is reduced, suggesting the involvement of a G protein-coupled receptor (GPCR). The amino-terminal “flexible tail” (FT, residues 23-120) of PrPC triggered a concentration-dependent cAMP increase in primary Schwann cells, in the Schwann-cell line SW10, and in Hek293T cells overexpressing the GPCR Gpr126/Adgrg6. In contrast, naïve HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the FT, and ablation of Gpr126 from SW10 cells abolished the FT-induced cAMP response. The FT contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist, type-IV collagen (Col4). A KKRPKPG-containing PrPC-derived peptide (FT23-50) sufficed to induce a Gpr126-dependent cAMP response in cells and mice, and improved myelination in hypomorphic Gpr126 zebrafish mutants. Substitution of the cationic residues with alanines abolished the biological activity of both FT23-50 and the respective Col4 peptide. We conclude that PrPC promotes myelin homeostasis through FT-mediated Gpr126 agonism. Besides clarifying the physiological role of PrPC, these observations are relevant to the pathogenesis of demyelinating polyneuropathies, common debilitating diseases with limited therapeutic options.