Expression of the Ebola Virus VP24 Protein Compromises the Integrity of the Nuclear Envelope and Induces a Laminopathy-Like Cellular Phenotype.
Expression of the Ebola Virus VP24 Protein Compromises the Integrity of the Nuclear Envelope and Induces a Laminopathy-Like Cellular Phenotype.
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DOI：
10.1128/mbio.00972-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Rivas C
中科院分区：
文献类型：
--
作者：
Vidal S;Sánchez-Aparicio M;Seoane R;El Motiam A;Nelson EV;Bouzaher YH;Baz-Martínez M;García-Dorival I;Gonzalo S;Vázquez E;Vidal A;Muñoz-Fontela C;García-Sastre A;Rivas C
埃博拉病毒(Ebola Virus，EBOV)VP24蛋白是一种核衣壳相关蛋白，可抑制干扰素基因的表达，抑制干扰素介导的抗病毒反应，阻止信号转导和转录激活因子1(STAT1)的核输入。鉴定其他EBOV VP24合作伙伴的蛋白质组学研究表明，核膜成分Emerin是VP24细胞相互作用组的一个潜在元件。在这里，我们进一步研究了这种相互作用及其对细胞生物学的影响。我们证明了VP24不仅与Emerin相互作用，而且还与核膜内的其他成分，如层蛋白A/C和层蛋白B相互作用。我们还发现，VP24减弱了Emerin与层蛋白A/C之间的相互作用，损害了核膜的完整性。这种破坏与核形态异常、DNA损伤反应的激活、细胞外信号调节激酶(ERK)的磷酸化和干扰素刺激基因15(ISG15)的诱导有关。有趣的是，VP24的表达还促进了层蛋白A/C和Emerin的共同作用因子--屏障自整合因子(BAF)的胞浆易位和下调，导致BAF调控的CSF1基因受到抑制。重要的是，我们发现EBOV感染导致了与核膜损伤相关的通路的激活，这与我们在表达VP24的细胞中观察到的结果一致。综上所述，我们在这里证明了VP24作用于核膜，导致细胞形态和功能的改变，概括了椎板病的几个特征。
Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1). Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B. We also show that VP24 diminishes the interaction between emerin and lamin A/C and compromises the integrity of the nuclear membrane. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, expression of VP24 also promoted the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), a common interactor of lamin A/C and emerin, leading to repression of the BAF-regulated CSF1 gene. Importantly, we found that EBOV infection results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. In summary, here we demonstrate that VP24 acts at the nuclear membrane, causing morphological and functional changes in cells that recapitulate several of the hallmarks of laminopathy diseases.