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IFN 反应中斑马鱼 IRF 家族成员的启动子结合和核保留特征。

Promoter Binding and Nuclear Retention Features of Zebrafish IRF Family Members in IFN Response.

机构信息

State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.

College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China.

出版信息

Front Immunol. 2022 Apr 6;13:861262. doi: 10.3389/fimmu.2022.861262. eCollection 2022.

DOI:10.3389/fimmu.2022.861262
PMID:35464458
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9019167/
Abstract

Interferon regulatory factors (IRFs) constitute a family of transcription factors that synchronize interferon (IFN) antiviral response through translocating to nucleus and binding to the promoters of IFN and IFN-stimulated genes (ISGs). Fish contain 11 IRF members; however, whether or how fish IRF family genes function in IFN response remains limited. Herein, we determine the regulatory roles of 11 zebrafish IRF family members in IFN response relevant to their subcellular localization and promoter binding. Zebrafish IRF family members display three patterns of constitutive localization, only in nucleus (IRF1/2/9/11), only in cytoplasm (IRF3/5/7), and largely in nucleus with small amounts in cytoplasm (IRF4b/6/8/10). DNA pull-down assays confirm that all zebrafish IRF proteins are capable to bind fish IFN promoters, albeit to various degrees, thus regulating IFN gene transcription as activators (IRF1/3/5/6/7/8/9/11) or repressors (IRF2/4b/10). Further characterization of distinct IFN gene activation reveals that IRF1/3/5/6/7/8/9/11 efficiently stimulate zebrafish IFNφ1 expression, and IRF1/7/11 are responsible for zebrafish IFNφ3 expression. Two conserved basic residues within the helix α3 of DNA binding domains (DBDs) contribute to constitutive or inducible nuclear import for all zebrafish IRF family members and DNA binding for most members, thereby enabling them to function as transcription factors. Our results reveal a conserved and general mechanism that specifies zebrafish IRF family proteins to nuclear import and DNA binding, thereby regulating fish IFN response.

摘要

干扰素调节因子 (IRF) 构成转录因子家族，通过转位到核内并与 IFN 和 IFN 刺激基因 (ISG) 的启动子结合，同步 IFN 抗病毒反应。鱼类含有 11 个 IRF 成员；然而，鱼类 IRF 家族基因在 IFN 反应中的作用方式仍有限。在此，我们确定了 11 种斑马鱼 IRF 家族成员在 IFN 反应中的调节作用，与其亚细胞定位和启动子结合有关。斑马鱼 IRF 家族成员显示出三种组成型定位模式，仅在核内 (IRF1/2/9/11)、仅在细胞质中 (IRF3/5/7)，以及主要在核内但有少量在细胞质中 (IRF4b/6/8/10)。DNA 拉下测定证实所有斑马鱼 IRF 蛋白都能够结合鱼类 IFN 启动子，但结合程度不同，从而作为激活剂 (IRF1/3/5/6/7/8/9/11) 或抑制剂 (IRF2/4b/10) 调节 IFN 基因转录。对不同 IFN 基因激活的进一步表征表明，IRF1/3/5/6/7/8/9/11 有效地刺激斑马鱼 IFNφ1 的表达，而 IRF1/7/11 负责斑马鱼 IFNφ3 的表达。DNA 结合域 (DBD) 内螺旋 α3 中的两个保守碱性残基有助于所有斑马鱼 IRF 家族成员的组成型或诱导性核输入以及大多数成员的 DNA 结合，从而使它们能够作为转录因子发挥作用。我们的结果揭示了一种保守而通用的机制，该机制指定了斑马鱼 IRF 家族蛋白的核输入和 DNA 结合，从而调节鱼类 IFN 反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/e59df2cf7b66/fimmu-13-861262-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/930c50105b54/fimmu-13-861262-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/1058e2c0ce4e/fimmu-13-861262-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/c95510519091/fimmu-13-861262-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/4bcdcfee4c22/fimmu-13-861262-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/2b6f875e6243/fimmu-13-861262-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/d7c80679387a/fimmu-13-861262-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/e59df2cf7b66/fimmu-13-861262-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/070e5116795b/fimmu-13-861262-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/9bdf0a699be5/fimmu-13-861262-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/d4e51ebe5a92/fimmu-13-861262-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/1058e2c0ce4e/fimmu-13-861262-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/c95510519091/fimmu-13-861262-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/4bcdcfee4c22/fimmu-13-861262-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/2b6f875e6243/fimmu-13-861262-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49e0/9019167/e59df2cf7b66/fimmu-13-861262-g010.jpg

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