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IFI16,一种核先天免疫 DNA 传感器,通过与 H3K9 甲基转移酶 SUV39H1 和 GLP 的结合,介导疱疹病毒基因组的表观遗传沉默。

IFI16, a nuclear innate immune DNA sensor, mediates epigenetic silencing of herpesvirus genomes by its association with H3K9 methyltransferases SUV39H1 and GLP.

机构信息

Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, United States.

Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, United States.

出版信息

Elife. 2019 Nov 4;8:e49500. doi: 10.7554/eLife.49500.

DOI:10.7554/eLife.49500
PMID:31682228
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6855800/
Abstract

IFI16, an innate immune DNA sensor, recognizes the nuclear episomal herpes viral genomes and induces the inflammasome and interferon-β responses. IFI16 also regulates cellular transcription and act as a DNA virus restriction factor. IFI16 knockdown disrupted the latency of Kaposi's sarcoma associated herpesvirus (KSHV) and induced lytic transcripts. However, the mechanism of IFI16's transcription regulation is unknown. Here, we show that IFI16 is in complex with the H3K9 methyltransferase SUV39H1 and GLP and recruits them to the KSHV genome during de novo infection and latency. The resulting depositions of H3K9me2/me3 serve as a docking site for the heterochromatin-inducing HP1α protein leading into the IFI16-dependent epigenetic modifications and silencing of KSHV lytic genes. These studies suggest that IFI16's interaction with H3K9MTases is one of the potential mechanisms by which IFI16 regulates transcription and establish an important paradigm of an innate immune sensor's involvement in epigenetic silencing of foreign DNA.

摘要

IFI16 是一种先天免疫 DNA 传感器,可识别核外痘病毒基因组,并诱导炎症小体和干扰素-β反应。IFI16 还调节细胞转录并作为 DNA 病毒限制因子。IFI16 敲低破坏了卡波西肉瘤相关疱疹病毒 (KSHV) 的潜伏期,并诱导了裂解转录物。然而,IFI16 转录调节的机制尚不清楚。在这里,我们表明 IFI16 与 H3K9 甲基转移酶 SUV39H1 和 GLP 形成复合物,并在从头感染和潜伏期将它们募集到 KSHV 基因组上。由此产生的 H3K9me2/me3 沉积作为异染色质诱导 HP1α 蛋白的停靠位点,导致 IFI16 依赖性表观遗传修饰和 KSHV 裂解基因的沉默。这些研究表明,IFI16 与 H3K9MTases 的相互作用是 IFI16 调节转录的潜在机制之一,并建立了先天免疫传感器参与外源 DNA 表观遗传沉默的重要范例。

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