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哈兽研首次发现猪源RNF114(pRNF114)具有抑制猪瘟病毒(CSFV)复制的功能

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发表于 2019-9-7 16:44:52 | 显示全部楼层 |阅读模式
近日,中国农业科学院哈尔滨兽医研究所兽医生物技术国家重点实验室猪烈性传染病创新团队经过系统研究,首次发现猪源RNF114(pRNF114)具有抑制猪瘟病毒(CSFV)复制的功能,并证实pRNF114通过泛素化降解CSFV NS4B蛋白进而抑制CSFV的复制。相关研究成果以发表于病毒学领域知名期刊《Journal of Virology》。

RNF114包含5个保守的结构域:RING结构、C2HC结构、2个C2H2锌指结构和UIM结构,RING区域赋予其E3泛素连接酶活性。目前,有报道称,人源RNF114参与调控RIG-I/MDA5信号通路、T细胞激活、细胞周期、细胞分化和衰老过程,鲜有文献报道RNF114与病毒的相互作用关系。基于前期的研究发现,pRNF114为潜在的抗CSFV宿主分子,但其调控CSFV复制的机制未知。
本研究首先证实,pRNF114的mRNA转录水平随着CSFV感染时间、感染剂量的增加而上调,说明pRNF114可能参与调控CSFV的复制。在pRNF114抗病毒功能方面,通过过表达及敲除pRNF114试验均证实,pRNF114是一种抗CSFV复制的宿主分子;在pRNF114抗CSFV分子机制方面,首先揭示pRNF114抑制CSFV复制依赖其E3泛素连接酶活性;其次证实pRNF114与CSFV NS4B蛋白存在直接的相互作用,并催化NS4B蛋白发生K27连接的聚泛素化修饰,进而通过蛋白酶体途径降解NS4B蛋白。本研究首次解析了pRNF114抗CSFV复制的分子机制,丰富了E3泛素连接酶直接抗病毒的功能。

Figure  pRNF114 interacts with the CSFV NS4B.
张越秀硕士和张华伟硕士为本研究的共同第一作者,李连峰副研究员和仇华吉研究员为共同通讯作者。该研究得到国家自然科学基金项目(31702220、31630080和31672537)、黑龙江省自然科学基金项目(QC2017027)及中国博士后基金项目(2017M620979)的资助。




Title:Porcine RING finger protein 114 inhibits classical swine fever virus replication via the K27-linked polyubiquitination of viral NS4B
DOI:10.1128/JVI.01248-19
Abstract:In the host, many RING-domain E3 ligases have been reported to inhibit viral replication through various mechanisms. In a previous screen, we found that the porcine RING finger protein 114 (pRNF114), an RING-domain E3 ubiquitin ligase, inhibits classical swine fever virus (CSFV) replication. This study aimed to clarify the underlying antiviral mechanism of pRNF114 against CSFV. Upon CSFV infection, the pRNF114 mRNA was upregulated both in vitro and in vivo. CSFV replication was significantly suppressed in PK-pRNF114 cells stably expressing pRNF114 by lentivirus-delivered system, whereas CSFV growth was enhanced in PK-15 cells with RNF114 knockout by the CRISPR/Cas9 system. The RING domain of pRNF114, which has the E3 ubiquitin ligase activity, is crucial for its antiviral activity. Mechanistically, pRNF114 interacted with the CSFV NS4B protein through their C-terminal domains, which led to the K27-linked polyubiquitination and degradation of NS4B through a proteasome-dependent pathway. Collectively, these findings indicate that pRNF114 as a critical regulator of CSFV replication and uncover a mechanism by which pRNF114 employs its E3 ubiquitin ligase activity to inhibit CSFV replication.

Importance: The porcine RING finger protein 114 (pRNF114) is a member of RING-domain E3 ligases. In this study, pRNF114 is a potential anti-CSFV factor and the anti-CSFV effect of pRNF114 depends on its E3 ligase activity. Notably, pRNF114 targets and catalyzes the K27-linked polyubiquitination of the NS4B protein and then promotes proteasome-dependent degradation of NS4B, inhibiting the replication of CSFV. To our knowledge, pRNF114 is the first E3 ligase to be identified as being involved in anti-CSFV activity and targeting NS4B could be a crucial route for antiviral development.


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 楼主| 发表于 2019-9-7 16:45:08 | 显示全部楼层
全文链接:

链接: https://pan.baidu.com/s/1J1cjRLAF0EwRi6dDn-CXCQ 提取码: srs5

1165

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593

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1755

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论坛区长

Rank: 9Rank: 9Rank: 9Rank: 9

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593
 楼主| 发表于 2019-9-7 16:45:12 | 显示全部楼层
全文链接:

链接: https://pan.baidu.com/s/1J1cjRLAF0EwRi6dDn-CXCQ 提取码: srs5
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