Substrate and enzyme trafficking as a means of regulating 1,25-dihydroxyvitamin D synthesis and action: The human innate immune response
Substrate and enzyme trafficking as a means of regulating 1,25-dihydroxyvitamin D synthesis and action: The human innate immune response
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DOI：
10.1359/jbmr.07s214
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发表时间：
2007-12-01
影响因子：
6.2
通讯作者：
Hewison, Martin
中科院分区：
文献类型：
--
作者：
Adams, John S.;Chen, Hong;Hewison, Martin
活性维生素D代谢物1，25-二羟基维生素D [1，25（OH）（2）D]的组织利用度取决于活化酶Ia-羟化酶（CYT 27 b1）及其分解代谢对应物24-羟化酶（CYP 24）的表达。这两种酶的活性反过来又受以下因素控制，包括血清维生素D结合蛋白（DBP）对25-羟基维生素D [25（OH）D]的亲和力;酶辅因子的可用性;以及表达的羟化酶基因产物的相对量。近年来，已经清楚的是，底物和酶的定向运输也是表达CYP 27 b1和CYP 24基因的肾和肾外组织的激素合成调节过程的关键组成部分。细胞外调节运输事件由进入循环池的底物25（OH）D的量定义。25（OH）D进入体内某些靶细胞，如巨噬细胞和近端肾小管上皮细胞，需要与血清DBP结合，然后被识别、内化和胞内释放。“释放的”细胞内底物被移动到特定的细胞内目的地（即，线粒体ATP酶和维生素D受体[VDR]）。1，25（OH），D的合成也受CYP 24及其代谢失活剪接变体CYP 24-SV的调节。最后，1，25（OH）（2）D调节基因（如CYP 24）的转录起始需要将CYP 27 b1产物1，25（OH）2D移动至同一细胞中的VDR，以进行内分泌作用或输出至另一细胞以进行旁分泌作用。在任何一种情况下，1，25（OH）2D配体都是VDR与类维生素A X受体异二聚化所必需的，并竞争显性负作用的、异质核核糖核蛋白（hnRNP）相关的维生素D反应元件结合蛋白，其抑制基因的转录。在这篇综述中，我们使用维生素D导向的人类先天性免疫反应结核分枝杆菌作为一个生理相关的模型系统，突出这些细胞内交通模式的重要性。
Tissue availability of the active vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] is dependent on expression of the activating enzyme la-hydroxylase (CYT27b1) and its catabolic counterpart 24-hydroxylase (CYP24). The activity of these two enzymes is in turn controlled by factors including affinity of the serum vitamin D-binding protein (DBP) for 25-hydroxyvitamin D [25(OH)D]; the availability of enzyme cofactors; and the relative amount of hydroxylase gene product expressed. In recent years, it has become clear that directed trafficking of substrate and enzyme is also a pivotal component of the regulated process of hormone synthesis by both renal and extrarenal tissues expressing the CYP27b1 and CYP24 genes. Extracellular regulatory trafficking events are defined by the quantity of substrate 25(OH)D entering the circulatory pool. Entry into some target cells in vivo, such as the macrophage and proximal renal tubular epithelial cells, requires 25(OH)D binding to serum DBP, followed by recognition, internalization, and intracellular release. The "released" intracellular substrate is moved to specific intracellular destinations (i.e., the mitochondrial CYP enzymes and the vitamin D receptor [VDR]) by the hsc70 family of chaperone proteins. Synthesis of 1,25(OH),D is also regulated by CYP24 and its metabolically inactive splice variant CYP24-SV. Finally, initiation of transcription of 1,25(OH)(2)D-regulated genes, such as the CYP24, requires movement of the CYP27b1 product, 1,25(OH)2D, to the VDR in the same cell for intracrine action or export to another cell for paracrine action. In either case, the 1,25(OH)2D ligand is required for the VDR to heterodimerize with the retinoid x receptor and compete away the dominant-negative acting, heterogeneous nuclear ribonucleoprotein (hnRNP)-related, vitamin D response element-binding proteins that inhibit hormone-directed transactivation of genes. In this review, we use vitamin D-directed events in the human innate immune response to Mycobacterium tuberculosis as a physiologically relevant model system in which to highlight the importance of these intracellular traffic patterns.