The final stage of Ebola virus (EBOV) replication is budding from host cells, where the matrix protein VP40 is essential for driving this process. Many post-translational modifications such as ubiquitination are involved in VP40 egress, but acetylation has not been studied yet. Here, we characterize NEDD4 is acetylated at a conserved Lys667 mediated by the acetyltransferase P300 which drives VP40 egress process. Importantly, P300-mediated NEDD4 acetylation promotes NEDD4-VP40 interaction which enhances NEDD4 E3 ligase activity and is essential for the activation of VP40 ubiquitination and subsequent egress. Finally, we find that Zaire ebolavirus production is dramatically reduced in P300 knockout cell lines, suggesting that P300-mediated NEDD4 acetylation may have a physiological effect on Ebola virus life cycle. Thus, our study identifies an acetylation-dependent regulatory mechanism that governs VP40 ubiquitination and provides insights into how acetylation controls EBOV VP40 egress.

中文翻译：

---

P300 介导的 NEDD4 乙酰化通过增强 NEDD4 连接酶活性来驱动埃博拉病毒 VP40 流出。

埃博拉病毒 (EBOV) 复制的最后阶段是从宿主细胞萌芽，其中基质蛋白 VP40 对驱动这一过程至关重要。许多翻译后修饰如泛素化与 VP40 出口有关，但尚未研究乙酰化。在这里，我们表征 NEDD4 在保守的 Lys667 乙酰化，由乙酰转移酶 P300 介导，该酶驱动 VP40 流出过程。重要的是，P300 介导的 NEDD4 乙酰化促进了 NEDD4-VP40 相互作用，这增强了 NEDD4 E3 连接酶活性，并且对于 VP40 泛素化和随后的出口至关重要。最后，我们发现在 P300 敲除细胞系中扎伊尔埃博拉病毒的产生显着减少，这表明 P300 介导的 NEDD4 乙酰化可能对埃博拉病毒的生命周期产生生理影响。因此，