E3 连接酶 Itch 是造血干细胞自我平衡和功能的负调控因子。
The E3 ligase Itch is a negative regulator of the homeostasis and function of hematopoietic stem cells.
机构信息
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
出版信息
Nat Immunol. 2011 May;12(5):399-407. doi: 10.1038/ni.2021. Epub 2011 Apr 10.
Abstract
Although hematopoietic stem cells (HSCs) are the most thoroughly characterized type of adult stem cell, the intricate molecular machinery that regulates their self-renewal properties remains elusive. Here we showed that the E3 ubiquitin ligase Itch negatively regulated the development and function of HSCs. Itch(-/-) mice had HSCs with enhanced frequency, competence and long-term repopulating activity. Itch-deficient HSCs showed accelerated proliferation rates and sustained progenitor properties, as well as more signaling by the transcription factor Notch1, due to more accumulation of activated Notch1. Knockdown of Notch1 in Itch-mutant HSCs resulted in reversion of the phenotype. Thus, we identify Itch as a previously unknown negative regulator of HSC homeostasis and function.
摘要
虽然造血干细胞 (HSCs) 是最彻底表征的成人干细胞类型，但调节其自我更新特性的复杂分子机制仍难以捉摸。在这里，我们表明 E3 泛素连接酶 Itch 负调控 HSCs 的发育和功能。Itch(-/-) 小鼠具有更高频率、更高能力和更长时间的造血干细胞重建活性。由于激活的 Notch1 积累更多，Itch 缺陷型 HSCs 显示出更快的增殖速度和持续的祖细胞特性，以及转录因子 Notch1 的更多信号。Notch1 在 Itch 突变型 HSCs 中的敲低导致表型逆转。因此，我们将 Itch 鉴定为 HSC 动态平衡和功能的一个以前未知的负调控因子。
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