Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Cell Line
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Ebolavirus / physiology
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Hemorrhagic Fever, Ebola / metabolism*
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Humans
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Nedd4 Ubiquitin Protein Ligases / metabolism*
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Viral Matrix Proteins / metabolism*
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Virus Release / physiology*
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p300-CBP Transcription Factors / metabolism*
Substances
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VP40 protein, virus
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Viral Matrix Proteins
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Nedd4 Ubiquitin Protein Ligases
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Nedd4 protein, human
Grants and funding
This research was supported by National Key R&D Program of China (2017YFA0505801 to M. C.), National Natural Science Foundation of China (81825015 to M. C., 81871650 to Y.Q. and 31630086 to M.C.), National Science and Technology Major Project (2018ZX10101004, to M. C.), and Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory (2019ACCP-MS06 to M. C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.