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Title: Redistribution of demethylated RNA helicase A during foot-and-mouth disease virus infection: role of jumonji C-domain containing protein 6 in RHA demethylation

Author
item LAWRENCE, PAUL - Oak Ridge Institute For Science And Education (ORISE)
item CONDERINO, JOSEPH - Oak Ridge Institute For Science And Education (ORISE)
item Rieder, Aida - Elizabeth

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/28/2013
Publication Date: 4/1/2014
Citation: Lawrence, P., Conderino, J., Rieder, A.E. 2014. Redistribution of demethylated RNA helicase A during foot-and-mouth disease virus infection: role of jumonji C-domain containing protein 6 in RHA demethylation. Virology. 452-453:1-11.

Interpretive Summary: Foot-and-mouth disease (FMD) is a devastating disease of livestock that is considered a high threat to US agriculture. Recently, ARS scientists working at the Plum Island Animal Disease Center identified a cellular protein (RHA) that the virus uses for its replication in the animal cells (Lawrence and Rieder 2009). In the current study, we provide new insight into the mechanism by which RHA is modified (by another host protein called JMJD6) in the infected cells and established a novel biochemical assay to demonstrate JMJD6 enzymatic activity. This information not only provides insight into the mechanisms of interaction between the animal cells and FMDV, but also could provide opportunities to devise antiviral strategies.

Technical Abstract: We previously reported that RNA Helicase A (RHA) re-localized from the nucleus to the cytoplasm in foot-and-mouth disease virus (FMDV) infected cells, coincident with a reduction in methylation of arginine residues in the RHA C-terminus. To further define the mechanism of RHA demethylation in FMDV-infected cells, we investigated the potential interaction between RHA and Jumonji C-domain (JmjC) containing protein 6 (JMJD6). Work described herein demonstrated that treatment with N-oxalylglycine, an inhibitor of the JmjC family of protein demethylases, not only prevented FMDV-induced RHA demethylation and re-localization, but also decreased viral protein synthesis and lowered virus titers. Western blot analysis showed host cells express mono and multimeric forms of JMJD6, and in FMDV-infected cells, RHA preferentially interacted with JMJD6 monomers. Immunolocalization studies showed the nuclear efflux of demethylated RHA (DM-RHA) was coincident with the nuclear influx of JMJD6, which appears FMDV-specific since a related picornavirus did not stimulate the same redistribution pattern. Here, we established a novel in vitro arginine demethylase assay, and demonstrated JMJD6-induced demethylation of RHA and two RHA-derived splice variants, in a dose-dependent manner. These observations allow us to propose a model in which FMDV infection induce JMJD6 interaction with RHA resulting in RHA demethylation followed by cytoplasmic re-localization, to facilitate DM-RHA enhancement of virus replication.