Virulence Factor NSs of Rift Valley Fever Virus Recruits the F-Box Protein FBXO3 To Degrade Subunit p62 of General Transcription Factor TFIIH
Virulence Factor NSs of Rift Valley Fever Virus Recruits the F-Box Protein FBXO3 To Degrade Subunit p62 of General Transcription Factor TFIIH
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DOI：
10.1128/jvi.02914-13
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发表时间：
2014-03-01
影响因子：
5.4
通讯作者：
Weber, Friedemann
中科院分区：
文献类型：
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作者：
Kainulainen, Markus;Habjan, Matthias;Weber, Friedemann
裂谷热病毒（RVFV;布尼亚病毒科，白蛉病毒属）是非洲严重的家畜和人类病原体，其非结构蛋白NSs是RVFV的主要毒力因子。RVFV NS阻断抗病毒I型干扰素（IFN）的转录上调，并通过泛素/蛋白酶体途径破坏一般转录因子TFIII 1亚基p62。在这里，我们确定了E3泛素连接酶，F-box蛋白FBXO 3，作为一个宿主细胞相互作用的NS的一个亚基。小干扰RNA（siRNA）介导的FBXO 3耗竭拯救RVFV感染细胞中的p62蛋白水平，并将IFN转录提高1个数量级。NS与全长FBXO 3蛋白以及缺乏C-末端酸性和富含poly（R）结构域的截短同种型相互作用。这些亚型存在于细胞核和细胞质中。NS专门去除全长FBXO 3的核池，可能是由于降解过程中的消耗。F-box蛋白形成所谓SCF泛素连接酶的可变底物识别亚基，其还含有恒定组分Skpl、cullin 1（或cullin 7）和Rbxl。Skpl的siRNA敲低也保护p62免于降解，表明参与NS作用。然而，敲低cullin 1、cullin 7或Rbxl不能拯救NS对p62的降解。我们的数据表明，p62通过宿主细胞因子FBXO 3的酶促去除是RVFV抑制IFN的主要机制。
The nonstructural protein NSs is the main virulence factor of Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), a serious pathogen of livestock and humans in Africa. RVFV NSs blocks transcriptional upregulation of antiviral type I interferons (IFN) and destroys the general transcription factor TFIII1 subunit p62 via the ubiquitin/proteasome pathway. Here, we identified a subunit of E3 ubiquitin ligases, F-box protein FBXO3, as a host cell interactor of NSs. Small interfering RNA (siRNA)-mediated depletion of FBXO3 rescued p62 protein levels in RVFV-infected cells and elevated IFN transcription by 1 order of magnitude. NSs interacts with the full-length FBXO3 protein as well as with a truncated isoform that lacks the C-terminal acidic and poly(R)-rich domains. These isoforms are present in both the nucleus and the cytoplasm. NSs exclusively removes the nuclear pool of full-length FBXO3, likely due to consumption during the degradation process. F-box proteins form the variable substrate recognition subunit of the so-called SCF ubiquitin ligases, which also contain the constant components Skpl, cullin 1 (or cullin 7), and Rbxl. siRNA knockdown of Skpl also protected p62 from degradation, suggesting involvement in NSs action. However, knockdown of cullin 1, cullin 7, or Rbxl could not rescue p62 degradation by NSs. Our data show that the enzymatic removal of p62 via the host cell factor FBXO3 is a major mechanism of IFN suppression by RVFV.