Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3
Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3
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DOI：
10.1073/pnas.241516998
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发表时间：
2001-11-20
影响因子：
11.1
通讯作者：
Christensen, EI
中科院分区：
文献类型：
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作者：
Nykjaer, A;Fyfe, JC;Christensen, EI
类固醇激素是多种生物过程的中心调节剂。根据游离激素假说，类固醇通过被动扩散进入靶细胞。然而，最近我们证明，25（OH）维生素D-3复合到其血浆载体，维生素D-结合蛋白，进入肾近端小管受体介导的内吞作用。缺乏内吞受体巨蛋白的基因敲除小鼠会在尿液中丢失25（OH）维生素D-3，并发生骨病。在这里，我们报告说，cubilin，膜相关蛋白与巨蛋白共定位，促进内吞过程中螯合类固醇载体复合物的细胞表面巨蛋白介导的内化cubilin结合的配体之前。患有影响cubilin生物合成的遗传性疾病的狗表现出异常的维生素D代谢。类似地，具有引起cubilin功能障碍的突变的人类患者表现出25（OH）维生素D-3的尿排泄。这一观察结果确定了影响细胞摄取和类固醇激素代谢的内吞受体途径中的自发突变。
Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D-3 complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D-3 in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D-3. This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.