The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function.
The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function.
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DOI：
10.1091/mbc.e16-08-0597
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发表时间：
2017-01-15
影响因子：
3.3
通讯作者：
Caplan MJ
中科院分区：
文献类型：
--
作者：
Padovano V;Kuo IY;Stavola LK;Aerni HR;Flaherty BJ;Chapin HC;Ma M;Somlo S;Boletta A;Ehrlich BE;Rinehart J;Caplan MJ
多囊蛋白由常染色体显性遗传性多囊肾病中突变的基因编码。提出了这些蛋白质在氧传感和细胞代谢中的新作用。氧调节多囊蛋白复合物的运输和通道活性，多囊蛋白复合物通过改变线粒体钙摄取来调节线粒体功能。常染色体显性遗传性多囊肾病是由多囊蛋白-1（PC 1）和多囊蛋白-2（PC 2）编码基因突变引起的，多囊蛋白-1和多囊蛋白-2形成离子通道复合物，其可介导纤毛感觉过程并调节内质网（ER）Ca 2+释放。PC 1表达的缺失深刻地改变了细胞的能量代谢。控制PC 1和PC 2贩运的机制，以及它们更广泛的生理作用，知之甚少。我们发现，O2水平通过与含O2敏感脯氨酰羟化酶结构域的蛋白EGLN 3（或PHD 3）（使PC 1羟化）的相互作用来调节多囊蛋白复合物的亚细胞定位和通道活性。此外，缺乏PC 1表达的细胞使用更少的O2，并显示更少的线粒体Ca 2+摄取，以响应缓激肽诱导的ER Ca 2+释放，表明PC 1可以调节线粒体功能。这些数据表明多囊蛋白在感知和响应细胞O2水平方面具有新的作用。
The polycystin proteins are encoded by the genes mutated in autosomal dominant polycystic kidney disease. A new role for these proteins in oxygen sensing and cell metabolism is proposed. Oxygen regulates the trafficking and channel activity of the polycystin complex, which modulates mitochondrial function by altering mitochondrial calcium uptake. Autosomal dominant polycystic kidney disease is caused by mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which form an ion channel complex that may mediate ciliary sensory processes and regulate endoplasmic reticulum (ER) Ca2+ release. Loss of PC1 expression profoundly alters cellular energy metabolism. The mechanisms that control the trafficking of PC1 and PC2, as well as their broader physiological roles, are poorly understood. We found that O2 levels regulate the subcellular localization and channel activity of the polycystin complex through its interaction with the O2-sensing prolyl hydroxylase domain containing protein EGLN3 (or PHD3), which hydroxylates PC1. Moreover, cells lacking PC1 expression use less O2 and show less mitochondrial Ca2+ uptake in response to bradykinin-induced ER Ca2+ release, indicating that PC1 can modulate mitochondrial function. These data suggest a novel role for the polycystins in sensing and responding to cellular O2 levels.