A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-MediatedExhaustion

A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-MediatedExhaustion

Abstract

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 dormantLT-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.

Authors: Xia P1, Wang S2, Ye B1, Du Y1, Li C1, Xiong Z3, Qu Y3, Fan Z4.

Influence Factor: 22.845

Citation: Immunity 48, 688-701.e687 (2018).

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