Regulation of Ebola virus VP40 matrix protein by SUMO

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.

Interaction of porcine reproductive and respiratory syndrome virus proteins with SUMO-conjugating enzyme reveals the SUMOylation of nucleocapsid protein

“…Substitution of this residue affects its functions, including interaction with PML, the ability to induce degradation of the PML NB-associated DAXX-ATRX chromatin-remodelling complex, and modulation of host p53 function and induction of cellular transformation [ 68 – 71 ]. The matrix protein VP40 of Ebola virus (EBOV) has been confirmed to be sumoylated, which not only maintains the stability of VP40, but also participates in the formation of virus-like particles (VLPs) [ 72 ]. The SUMOylation of influenza A virus NS1 has been shown to enhance the NS1 stability and its Ubc9-mediated SUMOylation is targeted for SUMO1, leading to promote the rapid growth of influenza A virus [ 73 ].…”

Regulation of the Ebola Virus VP24 Protein by SUMO

“…In vitro deSUMOylation assay. In vitro deSUMOylation assays with recombinant GST-SENP1 (Biomol) were performed on VP24-SUMO1 or VP24-SUMO2 as described previously (11).…”

“…One example is EBOV, which can exploit the SUMOylation machinery of the cell using both strategies. The EBOV VP35 protein induces SUMOylation of IRF7 and therefore inhibits the production of type I interferon (IFN) (10), and the EBOV major matrix VP40 protein is modified by SUMO, which contributes to its stability (11). Furthermore, EBOV can also exploit the ubiquitination pathway.…”

SUMO and Cytoplasmic RNA Viruses: From Enemies to Best Friends

“…In addition, EBOV hijacks the cellular SUMOylation system in order to modify its own proteins. Thus, the multifunctional VP40 protein, involved in regulating virus budding, nucleocapsid recruitment, virus structure and stability, and viral genome replication and transcription, is modified by SUMO [81]. Interestingly, SUMO was also found to be included into the viral particles formed by VP40.…”

“…Interestingly, SUMO was also found to be included into the viral particles formed by VP40. One consequence of VP40 SUMOylation is the regulation of its ubiquitination [81]. Although EBOV replication takes place in the cytoplasm of the infected cells, EBOV VP40 protein has been detected in the cell nucleus [82].…”