Two coupled mutations abolished the binding of CEBPB to the promoter of CXCL14 that displayed an antiviral effect on PRRSV by activating IFN signaling
Two coupled mutations abolished the binding of CEBPB to the promoter of CXCL14 that displayed an antiviral effect on PRRSV by activating IFN signaling
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两个偶联突变消除了 CEBPB 与 CXCL14 启动子的结合，CXCL14 通过激活 IFN 信号传导对 PRRSV 表现出抗病毒作用
DOI：
10.1096/fj.202000477r
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Xuewen Xu
中科院分区：
文献类型：
--
作者：
Lizhu Niu;Zhiwei Zheng;Qianjing Xue;Huijun Cheng;Ying Liu;Huanling Wang;Xueying Hu;Anding Zhang;Bang Liu;Xuewen Xu
猪繁殖与呼吸综合征（PRRS）是世界范围内最重要的猪传染性疾病。我们的前期研究发现桐城猪（TC）对PRRS的抗性高于大白猪（LW），但其遗传机制尚不清楚。在此，我们首先证实了CXCL14在猪肺和猪肺泡巨噬细胞（pam）中响应PRRS病毒（PRRSV）感染而下调，但LW猪的下调比TC猪更明显。然后，我们发现CXCL14的过表达通过上调干扰素β (IFNB)激活I型干扰素（IFN‐I）信号，而干扰素β在抗病毒作用中起主要作用。为了进一步解释其差异表达的机制，我们将CXCL14的核心启动子定位在转录起始位点（TSS）的- 145到276 bp之间，并鉴定出两个主要的单倍型，显示出显著的差异转录活性。我们进一步发现了两个偶联点突变，它们改变了CEBPB的结合状态，并导致TC和LW猪的差异表达。通过RNA干扰（RNAi）和染色质免疫沉淀（ChIP）进一步证实了CEBPB对CXCL14的调控作用，为解读异常情况下CXCL14下调的机制提供了重要线索。本研究揭示了CXCL14通过激活干扰素信号通路而产生的潜在抗病毒作用，并提示CXCL14有助于TC猪对PRRS的抗性。
Porcine reproductive and respiratory syndrome (PRRS) is the most economically important infectious disease of pigs worldwide. Our previous study revealed that Tongcheng (TC) pigs display higher resistance to PRRS than Largewhite (LW) pigs, but the genetic mechanism remains unknown. Here, we first confirmed that CXCL14 was downregulated in lungs and porcine alveolar macrophages (PAMs) responding to PRRS virus (PRRSV) infection, but the decline in LW pigs was more obvious than that in TC pigs. Then, we found that the overexpression of CXCL14 activated type‐I interferon (IFN‐I) signaling by upregulating interferon beta (IFNB), which plays a major role in the antiviral effect. To further decipher the mechanism underlying its differential expression, we characterized the core promoter of CXCL14 as being located from −145 to 276 bp of the transcription start site (TSS) and identified two main haplotypes that displayed significant differential transcriptional activities. We further identified two coupled point mutations that altered the binding status of CEBPB and were responsible for the differential expression in TC and LW pigs. The regulatory effect of CEBPB on CXCL14 was further confirmed by RNA interference (RNAi) and chromatin immunoprecipitation (ChIP), providing crucial clues for deciphering the mechanism of CXCL14 downregulation in unusual conditions. The present study revealed the potential antiviral effect of CXCL14, occurring via activation of interferon signaling, and suggested that CXCL14 contributes to the PRRS resistance of TC pigs.
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影响因子：
4.4
作者：
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作者：
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通讯作者：
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