Liu Zhenan, Yoon Joonho, Lee Eunyoung, Chang Audrey N, Miller R Tyler
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Medicine Service, VA North Texas Health Care System, Dallas, TX, USA.
FEBS Lett. 2025 Mar;599(6):866-875. doi: 10.1002/1873-3468.15078. Epub 2025 Jan 7.
Soluble, circulating Klotho (sKlotho) is essential for normal health and renal function. sKlotho is shed from the renal distal convoluted tubule (DCT), its primary source, via enzymatic cleavage. However, the physiologic mechanisms that control sKlotho production, trafficking, and shedding are not fully defined. We previously found that the G protein-coupled calcium-sensing receptor (CaSR) co-localizes with membrane-bound αKlotho and the disintegrin/metalloprotease ADAM10 in the DCT and controls sKlotho in response to CaSR ligands and pHo by activating ADAM10. Here, we advance understanding of this process by showing that tetraspanin 5 (Tspan5), a scaffolding and chaperone protein, contributes to the cell surface expression and specificity of a protein complex that includes Tspan5, ADAM10, Klotho, and CaSR. These results support a model of multiprotein complexes that confer signaling specificity beyond CaSR on G protein-coupled processes. Impact statement Systemic circulating sKlotho is a determinant for normal physiology. Studies of knockout animals established its role as an anti-aging protein. The regulatory mechanisms for Klotho production and secretion are largely unknown. We report that Tspan 5 contributes to CaSR- and ADAM10-dependent Klotho shedding from the kidney, its primary source.
可溶性循环型α-klotho蛋白（sKlotho）对正常健康和肾功能至关重要。sKlotho通过酶切作用从其主要来源——肾远曲小管（DCT）脱落。然而，控制sKlotho产生、运输和脱落的生理机制尚未完全明确。我们之前发现，G蛋白偶联的钙敏感受体（CaSR）与DCT中的膜结合型αKlotho和整合素/金属蛋白酶ADAM10共定位，并通过激活ADAM10来响应CaSR配体和pHo，从而控制sKlotho。在此，我们通过研究发现四跨膜蛋白5（Tspan5）（一种支架和伴侣蛋白）有助于包含Tspan5、ADAM10、Klotho和CaSR的蛋白复合物的细胞表面表达和特异性，从而进一步加深了对这一过程的理解。这些结果支持了一种多蛋白复合物模型，该模型赋予G蛋白偶联过程中超越CaSR的信号特异性。影响声明 全身循环的sKlotho是正常生理功能的一个决定因素。对基因敲除动物的研究确定了其作为抗衰老蛋白的作用。Klotho产生和分泌的调节机制在很大程度上尚不清楚。我们报告称，Tspan 5有助于肾脏（其主要来源）中CaSR和ADAM10依赖的Klotho脱落。
