IFI16 Isoforms with Cytoplasmic and Nuclear Locations Play Differential Roles in Recognizing Invaded DNA Viruses
IFI16 Isoforms with Cytoplasmic and Nuclear Locations Play Differential Roles in Recognizing Invaded DNA Viruses
复制标题
具有细胞质和核位置的 IFI16 同工型在识别入侵 DNA 病毒中发挥不同作用
DOI：
10.4049/jimmunol.2100398
复制
发表时间：
2021-12-01
影响因子：
4.4
通讯作者：
Ma, Feng
中科院分区：
文献类型：
--
作者：
Li, Dapei;Xie, Lifen;Ma, Feng
IFN-γ诱导蛋白16（IFI 16）识别来自核复制病毒和细胞质复制病毒的病毒DNA。具有核定位序列（NLS）的IFI 16的异构体2（IFI 16-iso 2）作为众所周知的DNA传感器已被广泛研究。然而，其他IFI 16亚型的特征和功能几乎是未知的。我们发现，IFI 16-iso 1与IFI 16-iso 2的长度完全相同，但缺乏NLS，定位于细胞质中。为了区分IFI 16-iso 1和IFI 16-iso 2的功能，我们开发了可以被核DNA传感器识别的新型核病毒DNA模拟物，包括IFI 16-iso 2和hnRNPA 2B 1。核定位序列（DNLS）的六核苷酸基序5 '-AGTGTT-3' DNA形式有效地驱动细胞质病毒DNA核转位。这些核病毒DNA模拟物在人A549细胞、HEK 293 T细胞和小鼠巨噬细胞中有效诱导IFN-β和抗病毒IFN刺激基因。IFI 16亚型的亚细胞位置差异决定了它们在识别病毒DNA和激活I型IFN依赖性抗病毒免疫中的差异功能。IFI 16-iso 1优先与细胞质HSV 60 mer和细胞质复制型痘苗病毒（VACV）共定位，而IFI 16-iso 2主要与核HSV 60-DNLS和核复制型HSV-1共定位。与IFI 16-iso 2相比，IFI 16-iso 1诱导更多的IFN-β和IFN刺激基因的转录，以及在HSV 60 mer转染或VACV感染时更强的抗病毒免疫。IFI 16-iso 2具有核质穿梭的能力，能显著清除侵入的HSV-1和VACV。然而，在HSV 60-DNLS转染或HSV 1型感染后，IFI 16-iso 2比IFI 16-iso 1诱导更多的I型IFN依赖性抗病毒免疫。我们的研究已经开发出有效的激动剂的核DNA传感器，也证明了IFI 16亚型与细胞质和核的位置发挥不同的作用，在先天免疫对DNA病毒。
IFN-gamma-inducible protein 16 (IFI16) recognizes viral DNAs from both nucleus-replicating viruses and cytoplasm-replicating viruses. Isoform 2 of IFI16 (IFI16-iso2) with nuclear localization sequence (NLS) has been studied extensively as a well-known DNA sensor. However, the characteristics and functions of other IFI16 isoforms are almost unknown. Here, we find that IFI16-iso1, with exactly the same length as IFI16-iso2, lacks the NLS and locates in the cytoplasm. To distinguish the functions of IFI16-iso1 and IFI16-iso2, we have developed novel nuclear viral DNA mimics that can be recognized by the nuclear DNA sensors, including IFI16-iso2 and hnRNPA2B1. The hexanucleotide motif 5'-AGTGTT-3' DNA form of the nuclear localization sequence (DNLS) effectively drives cytoplasmic viral DNA nuclear translocation. These nuclear viral DNA mimics potently induce IFN-beta and antiviral IFN-stimulated genes in human A549 cells, HEK293T cells, and mouse macrophages. The subcellular location difference of IFI16 isoforms determines their differential functions in recognizing viral DNA and activating type I IFN-dependent antiviral immunity. IFI16-iso1 preferentially colocalizes with cytoplasmic HSV60mer and cytoplasm-replicating vaccinia virus (VACV), whereas IFI16-iso2 mainly colocalizes with nuclear HSV60-DNLS and nucleus-replicating HSV-1. Compared with IFI16-iso2, IFI16-iso1 induces more transcription of IFN-beta and IFN-stimulated genes, as well as stronger antiviral immunity upon HSV60mer transfection or VACV infection. IFI16-iso2, with the ability of nuclear-cytoplasmic shuttling, clears both invaded HSV type 1 and VACV significantly. However, IFI16-iso2 induces more type I IFN-dependent antiviral immunity than IFI16-iso1 upon HSV60-DNLS transfection or HSV type 1 infection. Our study has developed potent agonists for nuclear DNA sensors and also has demonstrated that IFI16 isoforms with cytoplasmic and nuclear locations play differential roles in innate immunity against DNA viruses.