Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
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DOI：
10.1093/hmg/ddx283
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发表时间：
2017-10-15
影响因子：
3.5
通讯作者：
Rabe, Bjoern
中科院分区：
文献类型：
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作者：
Bartsch, Kareen;Knittler, Katharina;Rabe, Bjoern
DNA修复酶RNaseH2的亚型突变导致神经炎症性自身免疫性疾病艾卡迪古蒂斯综合征(AGS)。内源性核酸被认为积聚在患者细胞中，并激发致病性I型干扰素的表达。然而，在没有RNaseH2的情况下积累的潜在核酸物种还没有确定。在这里，我们报告了小鼠RNaseH2基因敲除细胞积累的胞浆DNA聚集物，几乎无法与微核区分。RNaseH2依赖的微核被核层包围，其中大部分含有受损的DNA。重要的是，它们诱导了干扰素刺激基因(ISGs)的表达，并与核酸传感器cGAS共定位。此外，与RNaseH2缺乏症相关的微核通过自噬被清除。因此，通过药物抑制mTOR诱导自噬导致胞浆DNA显著减少和伴随的干扰素签名。因此，自噬诱导可能是RNaseH2依赖疾病的一种可行的治疗选择。内源性逆转录因子以前被认为是AGS中触发免疫系统不适当激活的自身核酸的来源。我们使用CRISPR/Cas9产生的人RNaseH2基因敲除细胞来研究RNaseH2对逆转录元件增殖的影响。令人惊讶的是，在缺乏RNaseH2的细胞中，Line-1和Alu元件的复制被钝化，建立了RNaseH2作为动员内源性逆转座子的必要宿主因子。
Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder AicardiGoutie` res syndrome (AGS). Endogenous nucleic acids are believed to accumulate in patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet. Here, we report that murine RNase H2 knockout cells accumulated cytosolic DNA aggregates virtually indistinguishable from micronuclei. RNase H2-dependent micronuclei were surrounded by nuclear lamina and most of them contained damaged DNA. Importantly, they induced expression of interferon-stimulated genes (ISGs) and co-localized with the nucleic acid sensor cGAS. Moreover, micronuclei associated with RNase H2 deficiency were cleared by autophagy. Consequently, induction of autophagy by pharmacological mTOR inhibition resulted in a significant reduction of cytosolic DNA and the accompanied interferon signature. Autophagy induction might therefore represent a viable therapeutic option for RNase H2-dependent disease. Endogenous retroelements have previously been proposed as a source of self-nucleic acids triggering inappropriate activation of the immune system in AGS. We used human RNase H2-knockout cells generated by CRISPR/Cas9 to investigate the impact of RNase H2 on retroelement propagation. Surprisingly, replication of LINE-1 and Alu elements was blunted in cells lacking RNase H2, establishing RNase H2 as essential host factor for the mobilisation of endogenous retrotransposons.