Autophagy Driven by a Master Regulator of Hematopoiesis
Autophagy Driven by a Master Regulator of Hematopoiesis
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DOI：
10.1128/mcb.06166-11
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Bresnick, Emery H.
中科院分区：
文献类型：
--
作者：
Kang, Yoon-A;Sanalkumar, Rajendran;Bresnick, Emery H.
细胞器的发育和动态平衡重塑是由一个称为自噬的复杂过程所介导的。构成自噬机制的一组蛋白质在多步生化途径中发挥作用。虽然自噬机制的组成部分被广泛表达，但自噬可以在特殊的细胞环境中发生，而特定细胞类型自噬的潜在机制却知之甚少。我们证明了造血的主要调节因子GATA-1直接激活编码基本自噬成分微管相关蛋白1轻链3B(LC3B)及其同系物(MAP1LC3A、GABARAP、GABARAPL1和GATE-16)的基因的转录。此外，GATA-1直接激活参与溶酶体生物发生/功能的基因，介导自噬蛋白的周转。我们证明GATA-1利用叉头蛋白FOX03激活特定的自噬基因。依赖于GATA-1的LC3B的诱导与活性形式的LC3B和自噬小体的积累密切相关，自噬小体介导线粒体清除是红细胞生成的关键步骤。这些结果说明了一种新的机制，通过这种机制，发育的主要调节者建立了一个遗传网络，以激发特定细胞类型的自噬。
Developmental and homeostatic remodeling of cellular organelles is mediated by a complex process termed autophagy. The cohort of proteins that constitute the autophagy machinery functions in a multistep biochemical pathway. Though components of the autophagy machinery are broadly expressed, autophagy can occur in specialized cellular contexts, and mechanisms underlying cell-type-specific autophagy are poorly understood. We demonstrate that the master regulator of hematopoiesis, GATA-1, directly activates transcription of genes encoding the essential autophagy component microtubule-associated protein 1 light chain 3B (LC3B) and its homologs (MAP1LC3A, GABARAP, GABARAPL1, and GATE-16). In addition, GATA-1 directly activates genes involved in the biogenesis/function of lysosomes, which mediate autophagic protein turnover. We demonstrate that GATA-1 utilizes the forkhead protein FoxO3 to activate select autophagy genes. GATA-1-dependent LC3B induction is tightly coupled to accumulation of the active form of LC3B and autophagosomes, which mediate mitochondrial clearance as a critical step in erythropoiesis. These results illustrate a novel mechanism by which a master regulator of development establishes a genetic network to instigate cell-type-specific autophagy.