Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Virol. 2022 Mar 23;96(6):e0202621. doi: 10.1128/jvi.02026-21. Epub 2022 Feb 2.
Ebola virus (EBOV) and Marburg virus (MARV) continue to emerge and cause severe hemorrhagic disease in humans. A comprehensive understanding of the filovirus-host interplay will be crucial for identifying and developing antiviral strategies. The filoviral VP40 matrix protein drives virion assembly and egress, in part by recruiting specific WW domain-containing host interactors via its conserved PPxY late (L) domain motif to positively regulate virus egress and spread. In contrast to these positive regulators of virus budding, a growing list of WW domain-containing interactors that negatively regulate virus egress and spread have been identified, including BAG3, YAP/TAZ, and WWOX. In addition to host WW domain regulators of virus budding, host PPxY-containing proteins also contribute to regulating this late stage of filovirus replication. For example, angiomotin (AMOT) is a multi-PPxY-containing host protein that functionally interacts with many of the same WW domain-containing proteins that regulate virus egress and spread. In this report, we demonstrate that host WWOX, which negatively regulates egress of VP40 virus-like particles (VLPs) and recombinant vesicular stomatitis virus (VSV) M40 virus, interacts with and suppresses the expression of AMOT. We found that WWOX disrupts AMOT's scaffold-like tubular distribution and reduces AMOT localization at the plasma membrane via lysosomal degradation. In sum, our findings reveal an indirect and novel mechanism by which modular PPxY-WW domain interactions between AMOT and WWOX regulate PPxY-mediated egress of filovirus VP40 VLPs. A better understanding of this modular network and competitive nature of protein-protein interactions will help to identify new antiviral targets and therapeutic strategies. Filoviruses (Ebola virus [EBOV] and Marburg virus [MARV]) are zoonotic, emerging pathogens that cause outbreaks of severe hemorrhagic fever in humans. A fundamental understanding of the virus-host interface is critical for understanding the biology of these viruses and for developing future strategies for therapeutic intervention. Here, we reveal a novel mechanism by which host proteins WWOX and AMOTp130 interact with each other and with the filovirus matrix protein VP40 to regulate VP40-mediated egress of virus-like particles (VLPs). Our results highlight the biological impact of competitive interplay of modular virus-host interactions on both the virus life cycle and the host cell.
埃博拉病毒（EBOV）和马尔堡病毒（MARV）继续出现并导致人类严重出血性疾病。全面了解丝状病毒与宿主的相互作用对于鉴定和开发抗病毒策略至关重要。丝状病毒 VP40 基质蛋白通过其保守的 PPxY 晚期（L）结构域基序募集特定的 WW 结构域蛋白，从而驱动病毒粒子的组装和出芽，部分地正向调节病毒的出芽和扩散。与这些正向调节病毒出芽的因子相反，越来越多的 WW 结构域蛋白已被鉴定为负向调节病毒出芽和扩散，包括 BAG3、YAP/TAZ 和 WWOX。除了宿主 WW 结构域调节病毒出芽外，宿主含 PPxY 的蛋白也有助于调节丝状病毒复制的晚期阶段。例如，血管生成素（AMOT）是一种含有多个 PPxY 的宿主蛋白，它与许多调节病毒出芽和扩散的 WW 结构域蛋白具有功能相互作用。在本报告中，我们证明了宿主 WWOX 可负向调节 VP40 病毒样颗粒（VLPs）和重组水疱性口炎病毒（VSV）M40 病毒的出芽，该蛋白与 AMOT 相互作用并抑制其表达。我们发现 WWOX 通过溶酶体降解破坏 AMOT 的支架样管状分布并减少 AMOT 在质膜上的定位。总之，我们的发现揭示了 AMOT 和 WWOX 之间模块化 PPxY-WW 结构域相互作用通过 AMOT 调节丝状病毒 VP40 VLPs 的 PPxY 介导出芽的间接和新颖机制。更好地理解这种模块化网络和蛋白质-蛋白质相互作用的竞争性本质将有助于鉴定新的抗病毒靶标和治疗策略。丝状病毒（埃博拉病毒[EBOV]和马尔堡病毒[MARV]）是人畜共患的新兴病原体，会导致人类严重出血性发热的爆发。深入了解病毒-宿主界面对于理解这些病毒的生物学特性以及开发未来的治疗干预策略至关重要。在这里，我们揭示了一种新的机制，即宿主蛋白 WWOX 和 AMOTp130 相互作用，以及与丝状病毒基质蛋白 VP40 相互作用，从而调节 VP40 介导的病毒样颗粒（VLPs）的出芽。我们的结果突出了模块化病毒-宿主相互作用的竞争相互作用对病毒生命周期和宿主细胞的生物学影响。
