环状RNA cia-cGAS阻止天然免疫受体cGAS识别自身DNA维持细胞稳态的分子机制

Innate immune cells are derived from hematopoietic stem cells located in the bone marrow, and their self-renewal and differentiation are regulated by type I interferons. cGAS is a crucial DNA sensor in innate immune system. It is not clear how nuclear cGAS avoids initiating type I interferon production through recognizing self-genomic DNA. Circular RNA is a group of newly discovered non-coding RNA in recent years, and its role in hematopoietic stem cells is not clear. We found that circular RNA cia-cGAS was highly expressed in hematopoietic stem cells, and its knockout in mice caused significant hematopoietic dysfunction. Cia-cGAS knockout changed the self-renewal of hematopoietic stem cells and elevated the expression of type I interferon genes. We have proved that cGAS was an associated protein of cia-cGAS. Based on these results, we will study on how cia-cGAS interacts with cGAS and inhibits its activity in hematopoietic stem cells , how cia-cGAS maintains hematopoiesis through regulating type I interferon production, which will unravel the molecular mechanism of cia-cGAS in preventing cGAS-mediated self-DNA recognition and deepen our understanding of the regulatory roles of circular RNAs in hematopoiesis.

免疫细胞是由骨髓中造血干细胞发育分化而来，造血干细胞的自我更新和发育分化受到Ｉ型干扰素的调控。DNA受体cGAS蛋白是固有免疫系统中识别外源DNA的重要识别受体。细胞核内cGAS如何避免识别自身基因组DNA激活Ｉ型干扰素的表达尚不清楚。环状RNA是新发现的一类非编码RNA，它在造血干细胞中的作用未见报道。我们发现，环状RNA cia-cGAS在造血干细胞中高表达，cia-cGAS敲除的小鼠表现出明显的造血功能障碍，与Ｉ型干扰素通路相关的基因表达明显升高。我们已证实cia-cGAS能够与cGAS蛋白结合。在此基础上，我们将深入探究cia-cGAS在造血干细胞中是如何通过与cGAS结合而抑制cGAS的活性，继而调节Ｉ型干扰素的产生来维持造血稳态，揭示cia-cGAS阻止cGAS识别自身DNA的分子机制，将加深我们对环状RNA调控造血功能的认识。

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系统恶性肿瘤。然而，造血干细胞如何维持其静止状态并避免I型干扰素（IFN）介导的衰竭仍然是个谜。在这里，我们定义了一种环状RNA，我们称之为cia-cGAS，它在长期造血干细胞（LT-HSC）的细胞核中高度表达。小鼠cia-cGAS缺乏导致骨髓中I型干扰素表达升高，导致休眠LT-HSC数量减少。在稳态条件下，cia-cGAS结合细胞核中的DNA传感器cGAS以阻断其合成酶活性，从而保护休眠LT HSC免受cGAS介导的耗竭。此外，cia-cGAS与cGAS的结合亲和力强于自身DNA，因此抑制了cGAS介导的LT-HSC中I型干扰素的产生。我们的发现揭示了cia-cGAS通过阻断其酶活性和阻止cGAS识别自身DNA以维持宿主内环境稳定来抑制核cGAS的机制。相关结果发表在国际著名医学杂志Immunity（2018）上。