A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion
A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion
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环状 RNA 保护休眠造血干细胞免受 DNA 传感器 cGAS 介导的耗竭
DOI：
10.1016/j.immuni.2018.03.016
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发表时间：
2018-04-17
期刊：
影响因子：
32.4
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Xia, Pengyan;Wang, Shuo;Fan, Zusen
破坏造血干细胞（HSC）自我更新和分化之间的平衡会导致骨髓衰竭或血液恶性肿瘤。然而，HSC如何维持其静止状态并避免I型干扰素（IFN）介导的衰竭仍然是难以捉摸的。在这里，我们定义了一种环状RNA，我们将其命名为cia-cGAS，它在长期（LT）-HSC的细胞核中高度表达。小鼠中的Cia-cGAS缺乏导致骨髓中I型IFN的表达升高，并导致休眠的LT-HSC的数量减少。在稳态条件下，cia-cGAS与细胞核中的DNA传感器cGAS结合，阻断其合酶活性，从而保护休眠的LT-HSC免受cGAS介导的衰竭。此外，cia-cGAS比自身DNA对cGAS具有更强的结合亲和力，因此抑制LT-HSC中cGAS介导的I型IFN的产生。我们的研究结果揭示了cia-cGAS通过阻断其酶活性并阻止cGAS识别自身DNA以维持宿主体内平衡来抑制核cGAS的机制。
Disrupting the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how HSCs sustain their quiescent state and avoid type I interferon (IFN)-mediated exhaustion remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly expressed in the nucleus of long-term (LT)-HSCs. Cia-cGAS deficiency in mice caused elevated expression of type I IFNs in bone marrow and led to decreased numbers of dormant LT-HSCs. Under homeostatic conditions, cia-cGAS bound DNA sensor cGAS in the nucleus to block its synthase activity, thereby protecting dormant LT-HSCs from cGAS-mediated exhaustion. Moreover, cia-cGAS harbored a stronger binding affinity to cGAS than self-DNA did and consequently suppressed cGAS-mediated production of type I IFNs in LT-HSCs. Our findings reveal a mechanism by which cia-cGAS inhibits nuclear cGAS by blocking its enzymatic activity and preventing cGAS from recognizing self-DNA to maintain host homeostasis.