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

•FMDV Lpro physically interacts with ADNP.•Binding of ADNP to IFN promoter is enhanced upon infection with wild type FMDV.•The presence of ADNP is required for maximal FMDV replication.•ADNP and Brg1 are processed in an Lpro dependent manner.

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 mass spectrometry. We show that Lpro can bind to ADNP in vitro and in cell culture. RNAi of ADNP 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-α 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 targeting ADNP and modulation of its transcription repressive function to decrease the expression of IFN and ISGs.