Center of Excellence in Stem Cell Biology and Regenerative Medicine (COBRE), Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
J Exp Med. 2013 Feb 11;210(2):225-32. doi: 10.1084/jem.20121762. Epub 2013 Jan 14.
Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for red blood cell production and exert important cytoprotective effects on select vascular, immune, and cancer cells. To discover novel EPO action modes, we profiled the transcriptome of primary erythroid progenitors. We report Serpina3g/Spi2A as a major new EPO/EPOR target for the survival of erythroid progenitors. In knockout mice, loss of Spi2A worsened anemia caused by hemolysis, radiation, or transplantation. EPO-induced erythropoiesis also was compromised. In particular, maturing erythroblasts required Spi2A for cytoprotection, with iron and reactive oxygen species as cytotoxic agents. Spi2A defects were ameliorated by cathepsin-B/L inhibition, and by genetic co-deletion of lysosomal cathepsin B. Pharmacological inhibition of cathepsin B/L enhanced EPO-induced red cell formation in normal mice. Overall, we define an unexpected EPO action mode via an EPOR-Spi2A serpin-cathepsin axis in maturing erythroblasts, with lysosomal cathepsins as novel therapeutic targets.
促红细胞生成素 (EPO) 及其细胞表面受体 (EPOR) 对于红细胞的生成至关重要，并对特定的血管、免疫和癌细胞发挥重要的细胞保护作用。为了发现新的 EPO 作用模式，我们对原代红细胞祖细胞的转录组进行了分析。我们报告 Serpina3g/Spi2A 是 EPO/EPOR 的一个主要新靶点，可促进红细胞祖细胞的存活。在敲除小鼠中，Spi2A 的缺失会加重因溶血、辐射或移植引起的贫血。EPO 诱导的红细胞生成也受到影响。特别是，成熟的红细胞需要 Spi2A 来进行细胞保护，铁和活性氧作为细胞毒性剂。组织蛋白酶 B/L 的抑制作用以及溶酶体组织蛋白酶 B 的基因共缺失可改善 Spi2A 的缺陷。组织蛋白酶 B/L 的药理学抑制作用增强了正常小鼠中 EPO 诱导的红细胞形成。总的来说，我们通过成熟红细胞中的 EPOR-Spi2A 丝氨酸蛋白酶抑制剂-组织蛋白酶轴定义了一种意想不到的 EPO 作用模式，溶酶体组织蛋白酶是新的治疗靶点。
