Protein of Viral Hemorrhagic Septicemia Virus Suppresses STAT1-Mediated MHC Class II Transcription to Impair Antigen Presentation in Sea Perch, Lateolabrax japonicus
Protein of Viral Hemorrhagic Septicemia Virus Suppresses STAT1-Mediated MHC Class II Transcription to Impair Antigen Presentation in Sea Perch, Lateolabrax japonicus
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DOI：
10.4049/jimmunol.2100939
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发表时间：
2022-03-01
影响因子：
4.4
通讯作者：
Jia, Kuntong
中科院分区：
文献类型：
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作者：
Lu, Xiaobing;Li, Wenxi;Jia, Kuntong
病毒入侵宿主后，APC 将 Ag 加工成短肽，供 MHC II 类 (MHC-II) 呈递。 CD4(+) T 细胞对 MHC-II 背景下的病毒衍生肽的识别启动了清除病毒的适应性免疫反应。作为一种生存本能，病毒已经进化出逃避 Ag 处理和呈递的机制。在这项研究中，我们发现 IFN-γ 通过 STAT1/IFN 调节因子 1 (IRF1)/CIITA 信号通路诱导海鲈脑细胞系内源性 MHC-II 表达。此外，病毒性出血性败血症病毒感染显着抑制IFN-γ诱导的IRF1、CIITA、MHC-II-α和MHC-II-β基因的表达。相比之下，尽管 STAT1 转录本上调，但矛盾的是，STAT1 蛋白水平却减弱了。此外，过表达分析表明，病毒性出血性败血症病毒 N 蛋白可阻断 IFN-γ 诱导的 IRF1、CIITA、MHC-II-α 和 MHC-II-β 基因的表达，但不能阻断 STAT1 基因。我们还发现N蛋白与STAT1相互作用并增强了蛋白质的整体泛素化水平，包括花鲈脑细胞中的STAT1。通过K48连接的泛素化增强STAT1的泛素化，导致其通过泛素-蛋白酶体途径降解，从而抑制STAT1的生物学功能。我们的研究表明，水生病毒与哺乳动物病毒一样，以低等脊椎动物中的银呈递为目标来逃避免疫。
Upon virus invasion of the host, APCs process Ags to short peptides for presentation by MHC class II (MHC-II). The recognition of virus-derived peptides in the context of MHC-II by CD4(+) T cells initiates the adaptive immune response for virus clearance. As a survival instinct, viruses have evolved mechanisms to evade Ag processing and presentation. In this study, we discovered that IFN-gamma induced endogenous MHC-II expression by a sea perch brain cell line through the STAT1/IFN regulatory factor 1 (IRF1)/CIITA signaling pathway. Furthermore, viral hemorrhagic septicemia virus infection significantly inhibited the IFN-gamma-induced expression of IRF1, CIITA, MHC-II-alpha, and MHC-II-beta genes. By contrast, although STAT1 transcript was upregulated, paradoxically, the STAT1 protein level was attenuated. Moreover, overexpression analysis revealed that viral hemorrhagic septicemia virus N protein blocked the IFN-gamma-induced expression of IRF1, CIITA, MHC-II-alpha, and MHC-II-beta genes, but not the STAT1 gene. We also found out that N protein interacted with STAT1 and enhanced the overall ubiquitination level of proteins, including STAT1 in Lateolabrax japonicus brain cells. Enhanced ubiquitination of STAT1 through K48-linked ubiquitination led to its degradation through the ubiquitin-proteasome pathway, thereby inhibiting the biological function of STAT1. Our study suggests that aquatic viruses target Ag presentation in lower vertebrates for immune evasion as do mammalian viruses.