KRAB-Zinc Finger Protein ZNF268a Deficiency Attenuates the Virus-Induced Pro-Inflammatory Response by Preventing IKK Complex Assembly
KRAB-Zinc Finger Protein ZNF268a Deficiency Attenuates the Virus-Induced Pro-Inflammatory Response by Preventing IKK Complex Assembly
复制标题
KRAB-锌指蛋白 ZNF268a 缺乏通过阻止 IKK 复合物组装来减弱病毒诱导的促炎症反应
DOI：
10.3390/cells8121604
复制
发表时间：
2019-12-01
期刊：
影响因子：
6
通讯作者：
Guo, Mingxiong
中科院分区：
文献类型：
--
作者：
Liu, Yi;Yin, Wei;Guo, Mingxiong
尽管在了解病毒诱导的 NF-κ B 依赖性促炎细胞因子如何调节方面取得了进展，但仍有一些因素和机制有待探索。我们的目的是揭示 KRAB-锌指蛋白 ZNF268a 与病毒感染时 NF-κ B 介导的细胞因子产生之间的关系。为此，我们使用一对 sgRNA 建立了 ZNF268a 敲除细胞系，这对 sgRNA 同时靶向 HEK293T 中 ZNF268 基因编码序列中的外显子 3。与野生型细胞相比，缺乏 ZNF268a 的 HEK293T 细胞在响应仙台病毒/水泡性口炎病毒（SeV/VSV）感染时在转录和蛋白质水平上表现出较少的细胞因子表达。与 HEK293T 一致，THP-1 细胞中 siRNA 敲低 ZNF268a 显着抑制炎症反应。从机制上讲，ZNF268a 通过靶向 IKK α 促进 NF-kappa B 激活，帮助维持 IKK 信号复合物，从而实现适当的 p65 磷酸化和核转位。综上所述，我们的数据表明 ZNF268a 在调节病毒诱导的促炎细胞因子的产生中发挥积极作用。通过与 IKK α 相互作用，ZNF268a 有助于维持 IKK 复合体亚基之间的关联，从而促进病毒感染时的 NF-κ B 信号转导。
Despite progress in understanding how virus-induced, NF-kappa B-dependent pro-inflammatory cytokines are regulated, there are still factors and mechanisms that remain to be explored. We aimed to uncover the relationship between KRAB-zinc finger protein ZNF268a and NF-kappa B-mediated cytokine production in response to viral infection. To this end, we established a ZNF268a-knockout cell line using a pair of sgRNAs that simultaneously target exon 3 in the coding sequence of the ZNF268 gene in HEK293T. HEK293T cells lacking ZNF268a showed less cytokine expression at the transcription and protein levels in response to Sendai virus/vesicular stomatitis virus (SeV/VSV) infection than wild-type cells. Consistent with HEK293T, knock-down of ZNF268a by siRNAs in THP-1 cells significantly dampened the inflammatory response. Mechanistically, ZNF268a facilitated NF-kappa B activation by targeting IKK alpha, helping to maintain the IKK signaling complex and thus enabling proper p65 phosphorylation and nuclear translocation. Taken together, our data suggest that ZNF268a plays a positive role in the regulation of virus-induced pro-inflammatory cytokine production. By interacting with IKK alpha, ZNF268a promotes NF-kappa B signal transduction upon viral infection by helping to maintain the association between IKK complex subunits.