ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.
ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.
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DOI：
10.1084/jem.20201833
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Albert ML
中科院分区：
文献类型：
--
作者：
Herzner AM;Khan Z;Van Nostrand EL;Chan S;Cuellar T;Chen R;Pechuan-Jorge X;Komuves L;Solon M;Modrusan Z;Haley B;Yeo GW;Behrens TW;Albert ML
HNRNPC通过屏蔽隐蔽的剪接位点来防止反向重复的Alu双链RNA释放到细胞质中。Herzner等人。研究发现，HNRNPC基因缺失导致剪接功能紊乱和内含子双链RNA丰度增加，与ADAR缺失共同导致依赖MDA5的自发干扰素应答协同增加。胞质双链RNA(DsRNA)启动I型干扰素反应。内源性逆转录元素，特别是Alu元素，构成了dsRNA的来源。ADAR的腺苷-肌苷(A-to-I)编辑会导致dsRNA的错配，并阻止MDA5的识别和自身炎症。为了确定更多的内源性dsRNA检查点，我们在THP-1单核细胞中进行了候选筛选，发现HNRNPC和ADAR缺乏导致协同诱导依赖MDA5的干扰素反应。RNA-seq分析表明，HNRNPC缺陷细胞中包含Alu的内含子通过利用未掩蔽的隐蔽剪接位点，包括包含依赖ADAR的A-to-I编辑簇的内含子而失调。这些假定的MDA5配体在没有ADAR的情况下显示编辑减少，为HNRNPC和ADAR的联合作用提供了一种可信的机制。这项研究有助于我们理解重复元件诱导的自体炎症的控制，并表明HNRNPC突变的肿瘤患者可能最大限度地受益于基于ADAR抑制的免疫治疗。
hnRNPC prevents release of inverted-repeat Alu double-stranded RNA into the cytosol by masking cryptic splice sites. Herzner et al. found that deficiency in hnRNPC led to dysregulation of splicing and increased abundance of intronic double-stranded RNA, which together with ADAR deficiency resulted in a synergistic increase in spontaneous MDA5-dependent IFN responses. Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, providing a plausible mechanism for the combined effects of hnRNPC and ADAR. This study contributes to our understanding of the control of repetitive element–induced autoinflammation and suggests that patients with hnRNPC-mutated tumors might maximally benefit from ADAR inhibition-based immunotherapy.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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