Division of Hematology, Department of Medicine.
Molecular and Cellular Biology Program.
Blood Adv. 2022 Jun 28;6(12):3579-3589. doi: 10.1182/bloodadvances.2021005910.
Autophagy is a self-degradation pathway that is essential for erythropoiesis. During erythroid differentiation, autophagy facilitates the degradation of macromolecules and the programmed clearance of mitochondria. Impaired mitochondrial clearance results in anemia and alters the lifespan of red blood cells in vivo. While several essential autophagy genes contribute to autophagy in erythropoiesis, little is known about erythroid-specific mediators of this pathway. Genetic analysis of primary human erythroid and nonerythroid cells revealed the selective upregulation of the core autophagy gene ATG4A in maturing human erythroid cells. Because the function of ATG4A in erythropoiesis is unknown, we evaluated its role using an ex vivo model of human erythropoiesis. Depletion of ATG4A in primary human hematopoietic stem and progenitor cells selectively impaired erythroid but not myeloid lineage differentiation, resulting in reduced red cell production, delayed terminal differentiation, and impaired enucleation. Loss of ATG4A impaired autophagy and mitochondrial clearance, giving rise to reticulocytes with retained mitochondria and autophagic vesicles. In summary, our study identifies ATG4A as a cell type-specific regulator of autophagy in erythroid development.
自噬是一种自我降解途径，对红细胞生成至关重要。在红细胞分化过程中，自噬促进大分子的降解和线粒体的程序性清除。线粒体清除受损会导致贫血，并改变体内红细胞的寿命。虽然几个必需的自噬基因参与了红细胞生成中的自噬，但对于该途径的红细胞特异性介质知之甚少。对原代人红细胞和非红细胞的遗传分析显示，核心自噬基因 ATG4A 在成熟的人红细胞中选择性地上调。由于 ATG4A 在红细胞生成中的功能未知，我们使用体外人红细胞生成模型评估了其作用。在原代人造血干细胞和祖细胞中耗尽 ATG4A 选择性地损害了红细胞但不损害髓系分化，导致红细胞生成减少、晚期分化延迟和去核受损。ATG4A 的缺失会损害自噬和线粒体清除，导致网织红细胞保留线粒体和自噬小泡。总之，我们的研究确定 ATG4A 为红细胞发育中自噬的细胞类型特异性调节剂。
