Study of modulation of anti-oxidative cellular response by VP24 proteins of Marburgvirus and Ebolavirus
Ebola (EBOV) and Marburgvirus (MARV) are responsible for severe hemorrhagic syndrome in primates, including humans. The lethality rate can reach 90%, and no vaccine or treatment is available to counteract these diseases. EBOV and MARV have similar genomic organization and thus are placed in a distinct family, Filoviridae. VP24 is one of the 7 structural proteins which form the virion and has been shown to play an important role in assembly and condensation of viral nucleocapsids. VP24 of EBOV is responsible for prevention of cellular response to IFN. Mutations in EBOV VP24 gene are necessary for the adaptation to a new host. EBOV VP24 thus acts as a multifunctional factor. Available data suggest that MARV VP24 is not implicated in either the counteraction of IFN response, or in the adaptation process. In order to discover new functions for VP24 of MARV, we searched for its interaction with cellular proteins, using a yeast-double hybrid approach. We discovered an interaction between MARV VP24 and Keap1 protein and further confirmed this interaction in mammalian cells. Keap1 is a cellular protein involved in intracellular detection of Reactive Oxygen Species (ROS) and in the control of oxidative stress response. It inhibits the Nrf2 transcription factor, which regulates expression of antioxidant enzymes. Our results indicate that Keap1 binding domain for VP24 is the same as the one involved in Nrf2 binding, resulting in activation of transcriptional activity of Nrf2. Impact of MARV VP24 on ERRa, another target of Keap1, was also measured, as well as Nrf2 activity during EBOV infection. Our results showed that VP24 of EBOV and MARV have opposite effect on Nrf2 activity.