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Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (FMDV)

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Title: Interaction between FMDV Lpro and transcription factor ADNP is required for viral replication

item MEDINA, GISELLE - Oak Ridge Institute For Science And Education (ORISE)
item KNUDSEN, GISELLE - University Of California
item GRENINGER, ALEXANDER - Howard Hughes Medical Institute
item KLOC, ANNA - Oak Ridge Institute For Science And Education (ORISE)
item DIAZ-SAN SEGUNDO, FAYNA - University Of Connecticut
item Rieder, Aida - Elizabeth
item GRUBMAN, MARVIN - Retired ARS Employee
item DERISI, JOSEPH - Howard Hughes Medical Institute
item De Los Santos, Teresa

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/13/2017
Publication Date: 2/17/2017
Citation: Medina, G.N., Knudsen, G.M., Greninger, A.L., Kloc, A., Diaz-San Segundo, F., Rieder, A.E., Grubman, M., Derisi, J.L., De Los Santos, T.B. 2017. Interaction between FMDV Lpro and transcription factor ADNP is required for viral replication. Virology. 505:12-22. doi: 10.1016/j.virol.2017.02.010.

Interpretive Summary: Foot and mouth disease (FMD) remains one of the most devastating diseases that affect livestock worldwide. In collaboration with scientists at UCSF we have identified a cellular factor that interacts with “Leader (Lpro)”, an FMD virus (FMDV) protein. This factor known as ADNP (activity dependent neuroprotective protein) represses the expression of interferon by interacting with other host factors involved in condensing nuclear DNA (chromatin). Infection with FMDV contributes to the repressor activity of ADNP thus decreasing the production of interferon and other antiviral genes. This interaction uncovers a new novel mechanism by which Lpro modulates the host innate immune response.

Technical Abstract: The foot-and-mouth disease virus (FMDV) leader protease (Lpro) inhibits host translation and transcription affecting the expression of several factors involved in innate immunity. In this study, we have identified the host transcription factor ADNP (activity dependent neuroprotective protein) as an Lpro interacting protein by affinity purification/mass spectrometry. We show that Lpro can bind to ADNP in vitro and in cell culture. Depletion of ADNP by RNAi negatively affected virus replication and higher levels of interferon (IFN) and IFN-stimulated gene expression were detected. Importantly, infection with FMDV wild type but not with a virus lacking Lpro (leaderless), induced recruitment of ADNP to IFN-a promoter sites early during infection. Furthermore, we found that Lpro and ADNP are in a protein complex with the ubiquitous chromatin remodeling factor Brg-1. Our results uncover a novel role of FMDV Lpro in antagonizing the host innate immunity by targeting ADNP and modulating its transcriptional repressive function.