Malara Alessandro, Fresia Chiara, Di Buduo Christian Andrea, Soprano Paolo Maria, Moccia Francesco, Balduini Cesare, Zocchi Elena, De Flora Antonio, Balduini Alessandra
Departments of Molecular Medicine, Laboratories of Biotechnology, IRCCS San Matteo Foundation.
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova 16132, Italy.
J Biol Chem. 2017 Feb 24;292(8):3239-3251. doi: 10.1074/jbc.M116.751693. Epub 2017 Jan 3.
Abscisic acid (ABA) is a phytohormone involved in pivotal physiological functions in higher plants. Recently, ABA has been proven to be also secreted and active in mammals, where it stimulates the activity of innate immune cells, mesenchymal and hematopoietic stem cells, and insulin-releasing pancreatic β cells through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). In addition to behaving like an animal hormone, ABA also holds promise as a nutraceutical plant-derived compound in humans. Many biological functions of ABA in mammals are mediated by its binding to the LANCL-2 receptor protein. A putative binding of ABA to GRP78, a key regulator of endoplasmic reticulum stress, has also been proposed. Here we investigated the role of exogenous ABA in modulating thrombopoiesis, the process of platelet generation. Our results demonstrate that expression of both LANCL-2 and GRP78 is up-regulated during hematopoietic stem cell differentiation into mature megakaryocytes (Mks). Functional ABA receptors exist in mature Mks because ABA induces an intracellular Ca increase ([Ca] ) through PKA activation and subsequent cADPR generation. exposure of human or murine hematopoietic progenitor cells to 10 μm ABA does not increase recombinant thrombopoietin (rTpo)-dependent Mk differentiation or platelet release. However, under conditions of cell stress induced by rTpo and serum deprivation, ABA stimulates, in a PKA- and cADPR-dependent fashion, the mitogen-activated kinase ERK 1/2, resulting in the modulation of lymphoma 2 (Bcl-2) family members, increased Mk survival, and higher rates of platelet production. In conclusion, we demonstrate that ABA is a prosurvival factor for Mks in a Tpo-independent manner.
脱落酸（ABA）是一种参与高等植物关键生理功能的植物激素。最近，已证明ABA在哺乳动物中也有分泌且具有活性，它通过涉及第二信使环ADP - 核糖（cADPR）的信号通路刺激先天免疫细胞、间充质和造血干细胞以及胰岛素释放胰腺β细胞的活性。除了表现得像一种动物激素外，ABA作为一种源自植物的营养保健品在人类中也具有前景。ABA在哺乳动物中的许多生物学功能是通过其与LANCL - 2受体蛋白结合来介导的。也有人提出ABA与内质网应激的关键调节因子GRP78存在假定的结合。在这里，我们研究了外源性ABA在调节血小板生成（即血小板产生过程）中的作用。我们的结果表明，在造血干细胞分化为成熟巨核细胞（Mks）的过程中，LANCL - 2和GRP78的表达均上调。成熟Mks中存在功能性ABA受体，因为ABA通过PKA激活和随后的cADPR生成诱导细胞内Ca增加（[Ca] ）。将人或小鼠造血祖细胞暴露于10μm ABA不会增加重组血小板生成素（rTpo）依赖性的Mk分化或血小板释放。然而，在由rTpo和血清剥夺诱导的细胞应激条件下，ABA以PKA和cADPR依赖性方式刺激丝裂原活化蛋白激酶ERK 1/2，导致淋巴瘤2（Bcl - 2）家族成员的调节、Mk存活率增加以及更高的血小板产生率。总之，我们证明ABA是以Tpo非依赖性方式作为Mks的促存活因子。
