Abstract
The matrix protein of Ebola virus (EBOV) VP40 regulates viral budding, nucleocapsid recruitment, virus structure and stability, viral genome replication and transcription, and has an intrinsic ability to form virus-like particles. The elucidation of the regulation of VP40 functions is essential to identify mechanisms to inhibit viral replication and spread. Post-translational modifications of proteins with ubiquitin-like family members are common mechanisms for the regulation of host and virus multifunctional proteins. Thus far, no SUMOylation of VP40 has been described. Here we demonstrate that VP40 is modified by SUMO and that SUMO is included into the viral like particles (VLPs). We demonstrate that lysine residue 326 in VP40 is involved in SUMOylation, and by analyzing a mutant in this residue we show that SUMO conjugation regulates the stability of VP40 and the incorporation of SUMO into the VLPs. Our study indicates for the first time, to the best of our knowledge, that EBOV hijacks the cellular SUMOylation system in order to modify its own proteins. Modulation of the VP40-SUMO interaction may represent a novel target for the therapy of Ebola virus infection.
Highlights
The matrix protein of Ebola virus (EBOV) VP40 regulates viral budding, nucleocapsid recruitment, virus structure and stability, viral genome replication and transcription, and has an intrinsic ability to form virus-like particles
These results demonstrated that VP40 is SUMOylated in vitro by SUMO1 and SUMO2
Western-blot analysis of the purified extracts with anti-HA antibody revealed bands of the expected size corresponding to VP40-SUMO1 and VP40-SUMO2 only when cells were co-transfected with His6-SUMO1 or His6-SUMO2, respectively, indicating that VP40 is modified by SUMO1 and SUMO2 in transfected cells (Fig. 1B, left panel)
Summary
The matrix protein of Ebola virus (EBOV) VP40 regulates viral budding, nucleocapsid recruitment, virus structure and stability, viral genome replication and transcription, and has an intrinsic ability to form virus-like particles. We demonstrate that lysine residue 326 in VP40 is involved in SUMOylation, and by analyzing a mutant in this residue we show that SUMO conjugation regulates the stability of VP40 and the incorporation of SUMO into the VLPs. Our study indicates for the first time, to the best of our knowledge, that EBOV hijacks the cellular SUMOylation system in order to modify its own proteins. Post-translational modifications such as the conjugation of ubiquitin-like proteins can induce conformational changes of the target proteins enhancing its functional repertoire[11]. This is probably one of the reasons why viruses use the cellular SUMOylation and ubiquitination pathways to regulate their own proteins. Post-translational modifications with SUMO proteins involve isopeptide bond formation between the carboxyl group of the modifier and the ε-amino group of a lysine residue in the target. Modulation of the SUMO-VP40 interaction may represent a novel target for therapeutics to block EBOV infection
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