Filamin B restricts vaccinia virus spread and is targeted by vaccinia virus protein C4
Filamin B restricts vaccinia virus spread and is targeted by vaccinia virus protein C4
复制标题
DOI：
10.1128/jvi.01485-23
复制
发表时间：
2024-02-27
影响因子：
5.4
通讯作者：
Smith，Geoffrey L.
中科院分区：
文献类型：
--
作者：
Georgana，Iliana;Scutts，Simon R.;Smith，Geoffrey L.
牛痘病毒（VACV）是一种大的DNA病毒，其编码许多调节宿主免疫应答的蛋白质。VACV蛋白C4是一种已知抑制NF-κB信号级联和DNA-PK介导的DNA传感途径的活化的免疫调节剂。在这里，我们表明，C4的N-末端区域，既不抑制NF-κB，也不介导与DNA-PK的相互作用，仍然有助于病毒的毒力。此外，该结构域与细丝蛋白B（FLNB）的C末端结构域直接且以高亲和力相互作用。FLNB是一种大的肌动蛋白结合蛋白，稳定F-肌动蛋白网络，并参与其他细胞过程。从细胞中删除FLNB导致更大的VACV噬斑和增加的感染性病毒产量，表明FLNB限制VACV传播。这些数据表明，C4有一个新的功能，有助于毒力和从事细胞骨架。此外，我们表明，在VACV感染过程中，细胞骨架执行进一步的先前未表征的功能。重要的是，牛痘病毒（VACV），天花和猴痘的疫苗，编码许多蛋白质，以抵消宿主的免疫反应。研究这些蛋白质提供了对病毒免疫逃避机制的深入了解，从而表明如何设计更安全和更具免疫原性的VACV疫苗。在这里，我们报告的N-末端结构域的VACV蛋白C4直接与细胞骨架蛋白细丝蛋白B（FLNB）的相互作用，这一领域的C4有助于病毒的毒力。此外，VACV在缺乏FLNB的细胞中更好地复制和传播，从而证明FLNB具有抗病毒活性。VACV利用细胞骨架在细胞内和细胞间移动;然而，先前的研究表明C4不参与VACV的复制或传播。因此，C4与FLNB结合的原因不同，这表明细胞骨架在病毒感染期间具有进一步未表征的作用。
Vaccinia virus (VACV) is a large DNA virus that encodes scores of proteins that modulate the host immune response. VACV protein C4 is one such immunomodulator known to inhibit the activation of both the NF-κB signaling cascade and the DNA-PK-mediated DNA sensing pathway. Here, we show that the N-terminal region of C4, which neither inhibits NF-κB nor mediates interaction with DNA-PK, still contributes to virus virulence. Furthermore, this domain interacts directly and with high affinity to the C-terminal domain of filamin B (FLNB). FLNB is a large actin-binding protein that stabilizes the F-actin network and is implicated in other cellular processes. Deletion of FLNB from cells results in larger VACV plaques and increased infectious viral yield, indicating that FLNB restricts VACV spread. These data demonstrate that C4 has a new function that contributes to virulence and engages the cytoskeleton. Furthermore, we show that the cytoskeleton performs further previously uncharacterized functions during VACV infection.IMPORTANCEVaccinia virus (VACV), the vaccine against smallpox and monkeypox, encodes many proteins to counteract the host immune response. Investigating these proteins provides insights into viral immune evasion mechanisms and thereby indicates how to engineer safer and more immunogenic VACV-based vaccines. Here, we report that the N-terminal domain of VACV protein C4 interacts directly with the cytoskeletal protein filamin B (FLNB), and this domain of C4 contributes to virus virulence. Furthermore, VACV replicates and spreads better in cells lacking FLNB, thus demonstrating that FLNB has antiviral activity. VACV utilizes the cytoskeleton for movement within and between cells; however, previous studies show no involvement of C4 in VACV replication or spread. Thus, C4 associates with FLNB for a different reason, suggesting that the cytoskeleton has further uncharacterized roles during virus infection.