Legumain是一种溶酶体半胱氨酸蛋白酶,与越来越多的生理和病理生理过程有关。然而,调节legumain表达和功能的上游机制尚不清楚。这里,我们提供了体外和体内数据,表明维生素D3(VD3)增强了豆蔻素的表达和功能。反过来,legumain改变了VD3的生物利用度,可能通过维生素D结合蛋白(VDBP)的蛋白水解裂解。活性VD3(1,25(OH)2D3)增加了豆科的表达,活动,并在人骨髓基质细胞的成骨培养物中分泌。在体内也观察到了legumain的上调,由肝脏和脾脏中的豆类mRNA增加证明,以及用25(OH)D3(50µg/kg,皮下)与对照相比8天。此外,legumain的血清水平也升高。我们进一步表明,活性豆蔻素在体外裂解纯化的VDBP(55kDa),形成45kDa片段。在体内,在Lgmn-/-小鼠的肾脏或肝脏中未发现VDBP裂解,而VDBP在野生型对照小鼠(Lgmn+/+)中被切割。最后,豆素缺乏导致血浆25(OH)D3和总VD3水平升高,并改变了参与VD3代谢的关键肾脏酶(CYP24A1和CYP27B1)的表达。总之,建议在VD3和legumain之间进行监管相互作用。
Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data showing that vitamin D3 (VD3) enhances
legumain expression and function. In turn, legumain alters VD3 bioavailability, possibly through proteolytic cleavage of vitamin D binding protein (VDBP). Active VD3 (1,25(OH)2D3) increased legumain expression, activity, and secretion in osteogenic cultures of human bone marrow stromal cells. Upregulation of
legumain was also observed in vivo, evidenced by increased
legumain mRNA in the liver and spleen, as well as increased legumain activity in kidneys from wild-type mice treated with 25(OH)D3 (50 µg/kg, subcutaneously) for 8 days compared to a control. In addition, the serum level of
legumain was also increased. We further showed that active legumain cleaved purified VDBP (55 kDa) in vitro, forming a 45 kDa fragment. In vivo, no VDBP cleavage was found in kidneys or liver from legumain-deficient mice (Lgmn-/-), whereas VDBP was cleaved in wild-type control mice (Lgmn+/+). Finally, legumain deficiency resulted in increased plasma levels of 25(OH)D3 and total VD3 and altered expression of key renal enzymes involved in VD3 metabolism (CYP24A1 and CYP27B1). In conclusion, a regulatory interplay between VD3 and
legumain is suggested.