BUD13 Promotes a Type I Interferon Response by Countering Intron Retention in Irf7
BUD13 Promotes a Type I Interferon Response by Countering Intron Retention in Irf7
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DOI：
10.1016/j.molcel.2018.11.038
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发表时间：
2019-02-21
期刊：
影响因子：
16
通讯作者：
Baltimore, David
中科院分区：
文献类型：
--
作者：
Frankiw, Luke;Majumdar, Devdoot;Baltimore, David
内含子保留（IR）已成为基因表达控制的重要机制，但控制 IR 事件的因素仍知之甚少。我们在 Irf7 基因的一个内含子中观察到一致的 IR，并将 BUD13 鉴定为一种 RNA 结合蛋白，作用于该内含子以增加成功剪接的数量。 BUD13 缺乏与 IR 增加、成熟 Irf7 转录物和蛋白质水平降低有关，从而抑制 I 型干扰素反应，从而损害了 BUD13 缺陷巨噬细胞抵抗水泡性口炎病毒 (VSV) 感染的能力。对 BUD13 敲低和 BUD13 与 RNA 交联的整体分析揭示了一个内含子子集，其与 Irf7 中发现的内含子具有许多特征，并且以 BUD13 依赖性方式进行剪接。 BUD13 的缺陷导致含有此类内含子的基因的成熟转录本减少。因此，通过充当 IR 拮抗剂，BUD13 促进 IR 发生基因的表达。
Intron retention (IR) has emerged as an important mechanism of gene expression control, but the factors controlling IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified BUD13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in BUD13 was associated with increased IR, decreased mature Irf7 transcript and protein levels, and consequently a dampened type I interferon response, which compromised the ability of BUD13-deficient macrophages to withstand vesicular stomatitis virus (VSV) infection. Global analysis of BUD13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a BUD13-dependent manner. Deficiency of BUD13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, BUD13 facilitates the expression of genes at which IR occurs.