Ebola viral protein 24 (eVP24) is considered a multifunctional secondary matrix protein present in viral particles. The broad roles eVP24 performs involve the formation of fully functional and infectious viral particles, promotion of filamentous nucleocapsid formation, mediation of host responses to infection, and suppression of the host innate immune system. It has been noted that eVP24 function can overlap with that of two other viral proteins; eVP40 matrix protein which functions in virus budding, and eVP35 which is also associated with immune suppression.
History
Research
The first recorded human outbreak of Ebola virus disease was in 1976 and since then, there has been considerable effort to define the progression of the disease and the virus responsible. The history of Ebola virus characterization is rather short as most research on the mechanisms employed by the virus have occurred in the last two decades. This is due to the intensive biohazard containment required for laboratory studies of the virus and the difficulty in obtaining samples for study, particularly in common outbreak regions. The isolation of viral cDNAs has allowed research into viral gene products to progress. The genome of the Ebola virus was found to encode seven proteins: glycoprotein; nucleoprotein; matrix proteins, VP40 and VP24; nonstructural proteins, VP30 and VP35; and viral polymerase. The functions of the viral proteins remained the last to be well investigated. In particular, eVP24 remained the least studied for some time.
Characterization
eVP24 was initially described as a matrix protein that had similar properties and functions of eVP40. eVP24 was found to have characteristics of typical viral matrix proteins, such as a strong association with lipid bilayers and the ability to oligomerize to form tetramers. Like eVP40, eVP24 was found to be essential in virion assembly and budding. Later research indicated that the expression of eVP24 was required to switch from viral transcription and replication to virion assembly. A new role for eVP24 was found when its expression was monitored in rodent species where changes in eVP24 seemed to be responsible for enhancing virulence, indicating that adaption of Ebola in animal models occurs through mutations in eVP24. Additionally, eVP24 inhibits interferon signaling by competitively binding to karyopherins which blocks phosphorylated STAT1 nuclear import. In 2014, it was found that this mechanism interferes with the cells response to viral infection, which suppressed the innate immune response, allowing the virus to proliferate in the body.
Function
eVP24 disrupts the signaling pathway of STAT1. The STAT1 protein is phosphorylated by interferons in response to viral infection causing it to express a non-classical nuclear localization signal and bind to the importin protein karyopherin-α (KPNA). Once bound to KPNA, STAT1 is transported to the nucleus where it stimulates gene transcription in response to viral infection. Classical nuclear localization signals are bound by arms 2-4 or by 6-8 of KPNA while non-classical nuclear localization signals are bound by KPNA 1, 5 and 6 in arms 8-10 allowing non classical signals to be transported at the same time as classical signals, providing faster signaling of certain signals. The eVP24 protein operates by binding to KPNA preventing the binding of STAT1. As a result, STAT1 is not able to elicit an immune response, however nuclear import is able to proceed as normal which may be important for viral replication. This means that eVP24 prevents the activation of an immune response against the Ebola virus without sacrificing its ability to have viral components transported to the nucleus or the target cell. eVP24 provides Ebola with an advantages over other viruses which disrupt STAT1 because unlike most other viruses, eVP24 uses mimicry of the STAT1 protein. This makes it very unlikely for the host to develop an adaptation as mutations in KPNA which prevent eVP24 binding are also likely to prevent STAT1 signalling.