Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19, Lausanne, Switzerland.
Dana-Farber Cancer Institute, Boston, MA, USA.
Commun Biol. 2024 Oct 24;7(1):1383. doi: 10.1038/s42003-024-07053-0.
The Activin-A precursor dimer can be cleaved by furin, but how this proteolytic maturation is regulated in vivo and how it facilitates access to signaling receptors is unclear. Here, analysis in a syngeneic melanoma grafting model shows that without furin coexpression, Activin-A failed to accelerate tumor growth, correlating with failure of one or both subunits to undergo cleavage in signal-sending cells, even though compensatory processing by host cells nonetheless sustained elevated circulating Activin-A levels. In reporter assays, furin-independent cleavage of one subunit enabled juxtacrine Activin-A signaling, whereas completion of proteolytic maturation by coexpressed furin or by recipient cells stimulated contact-independent activity, crosstalk with BMP receptors, and signal inhibition by follistatin. Mechanistically, Activin-A processing was modulated by allosteric disulfide bonds flanking the furin site. Disruption of these disulfide linkages with the prodomain enabled Activin-A binding to cognate type II receptors independently of proteolytic maturation. Stepwise proteolytic maturation is a novel mechanism to control Activin-A protein interactions and signaling.
激活素-A 前体二聚体可被弗林蛋白酶切割，但这种蛋白水解成熟过程如何在体内受到调节，以及它如何促进信号受体的激活尚不清楚。在这里，在同种异体黑色素瘤移植模型中的分析表明，如果没有弗林蛋白酶的共表达，激活素-A 无法加速肿瘤生长，这与信号发送细胞中一个或两个亚基未能发生切割相关，尽管宿主细胞的补偿性处理仍然维持了升高的循环激活素-A 水平。在报告基因检测中，一个亚基的弗林蛋白酶非依赖性切割使激活素-A 发挥旁分泌信号作用，而共表达的弗林蛋白酶或受者细胞完成蛋白水解成熟则刺激了无接触活性、与 BMP 受体的串扰以及卵泡抑素的信号抑制。从机制上讲，激活素-A 的加工受到弗林蛋白酶位点侧翼的变构二硫键的调节。通过前肽破坏这些二硫键连接使激活素-A 能够与同源型 II 型受体结合，而无需蛋白水解成熟。逐步蛋白水解成熟是控制激活素-A 蛋白相互作用和信号的一种新机制。
