Nakagawa Masahiro Marshall, Thummar Keyur, Mandelbaum Jonathan, Pasqualucci Laura, Rathinam Chozha Vendan
Department of Genetics and Development, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.
Department of Genetics and Development, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032 Department of Genetics and Development, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.
J Exp Med. 2015 Feb 9;212(2):203-16. doi: 10.1084/jem.20132544. Epub 2015 Jan 26.
A balance between quiescence and proliferation is critical for proper maintenance of the hematopoietic stem cell (HSC) pool. Although a lot is known about hematopoiesis, molecular mechanisms that control HSC quiescence remain largely unknown. The ubiquitin-editing enzyme A20 functions as a central regulator of inflammation and adaptive immunity. Here, we show that a deficiency of A20 in the hematopoietic system causes anemia, lymphopenia, and postnatal lethality. Lack of A20 in HSCs results in diminished pool size, impaired radioprotection, defective repopulation, and loss of quiescence. A20-deficient HSCs display increased IFN-γ signaling, caused by augmented NF-κB activation. Strikingly, deletion of both IFN-γ and A20 in hematopoietic cells results in partial rescue of the HSC phenotype. We anticipate that our experiments will facilitate the understanding of mechanisms through which A20-mediated inflammatory signals control HSC quiescence and functions.
静止与增殖之间的平衡对于造血干细胞（HSC）库的正常维持至关重要。尽管人们对造血作用了解很多，但控制HSC静止的分子机制仍 largely未知。泛素编辑酶A20作为炎症和适应性免疫的核心调节因子发挥作用。在此，我们表明造血系统中A20的缺乏会导致贫血、淋巴细胞减少和出生后致死。HSC中缺乏A20会导致库大小减小、辐射防护受损、重建造血功能缺陷以及静止丧失。A20缺陷的HSC表现出由增强的NF-κB激活引起的IFN-γ信号增加。令人惊讶的是，造血细胞中IFN-γ和A20的双缺失导致HSC表型的部分挽救。我们预计我们的实验将有助于理解A20介导的炎症信号控制HSC静止和功能的机制。
