Journal
IMMUNITY
Volume 48, Issue 4, Pages 688-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.03.016
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Funding
- National Natural Science Foundation of China [91640203, 31530093, 31429001, 81722023, 31770939, 31570872, 81601361, 31671531, 31471386, 31771638]
- Beijing Natural Science Foundation [718006]
- Strategic Priority Research Programs of the Chinese Academy of Sciences [XDB19030203, XDA12020219]
- Youth Innovation Promotion Association CAS [2015073]
- China Postdoctoral Science Foundation [2015M571141]
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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.
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