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Title: The nuclear protein Sam68 is cleaved by the FMDV 3C protease redistributing Sam68 to the cytoplasm during FMDV infection of host cells

Author
item Lawrence, Paul
item Schafer, Elizabeth
item Rieder, Aida - Elizabeth

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/31/2011
Publication Date: 1/26/2012
Citation: Lawrence, P.J., Schafer, E.A., Rieder, A.E. 2012. The nuclear protein Sam68 is cleaved by the FMDV 3C protease redistributing Sam68 to the cytoplasm during FMDV infection of host cells. Virology. 425:40-52.

Interpretive Summary: In this study we demonstrate that the cellular host factor Sam68 is critical to the life cycle of Foot-and-Mouth Disease Virus (FMDV), and is re-localized from the cell nucleus to the cytoplasm during the course of FMDV infection. As infection progresses, increasing amounts of a truncated form of Sam68 is detected lacking the C-terminal nuclear localization signal (NLS), thus providing a mechanism for its nuclear egress distinct from what we previously reported for the cytoplasmic shift of RNA Helicase A (RHA). Interestingly, we discovered that Sam68 interacts with the FMDV 3C proteinase, which is potentially responsible for the C-terminal cleavage of Sam68. Additionally, we show that Sam68 binds the internal ribosomal entry site (IRES) within the 5’ non-translated region (NTR) of the FMDV genome, which suggests that Sam68 plays a role in the translation of virus gene products. To the best of our knowledge, this is the first reported instance of virus-induced proteolysis of Sam68 in any virus system.

Technical Abstract: Infection by a variety of viruses alters the nuclear-cytoplasmic trafficking of certain host cell proteins. In our continued search for interacting factors, we reported the re-localization of RNA helicase A (RHA) from the nucleus to the cytoplasm in cells infected with foot-and-mouth disease virus (FMDV). Infection with the related poliovirus shifts the subcellular distribution of another RNA-binding protein, Sam68, which has been reported to partner with RHA. We confirmed the importance of Sam68 to the life cycle of FMDV using Sam68-targeted siRNAs. Similar to poliovirus, FMDV infection stimulated the redistribution of Sam68 from the nucleus to the cytoplasm, where it accumulated in stress granules. The gradual cytoplasmic redistribution of Sam68 was coincident with the cleavage of its C-terminus containing the nuclear localization sequence, suggesting that the loss of the nuclear localization signal (NLS) triggers the re-localization of Sam68 to the cytoplasm. The cleavage of Sam68 appears to be mediated by the viral 3C protease (3C^pro), which were observed to co-localize by immunofluorescence and co-precipitated together from virus-infected cell lysates. Sam68 was also found to interact with the FMDV IRES, and siRNA-mediated reduction in Sam68 decreased the activity of the FMDV IRES suggesting that it augments the translation of the viral genome.