The effect of Coxsackie virus A9 infection on nuclear and nucleolar proteins

Picornaviuses replicate in the cytoplasm, but there is growing evidence that the cell nucleus is affected by infection e.g. transcription factor cleavage, relocation of nuclear proteins and alteration to nucleo-cytoplasmic shuttling. It was previously observed that Parechovirus genus members affect the distribution of the nuclear paraspeckle protein PS PC-1, which is an RNA-binding protein involved in splicing and RNA export. To investigate if this is a general feature of picornaviruses infection, coxsackie virus A9 (CAV-9) was studied. This is a typical member of the large and most medically-important picornavirus genera Enterovirus, which is genetically divergent from Parechovirus. Using an EGFP-PSPC-1 fusion, we found that infection changes the distribution of PS PC-1 from nuclear paraspeckles to cytoplasmic granules that do not seem to correspond to known cytoplasmic foci of RNA-binding proteins e.g. stress granules and P-bodies. They also do not correspond to CAV-9 replication complexes. Two other paraspeckle proteins (PSF and NONO) colocalise with PSPC-1 in these structures. The effect does not seem to be due to cleavage of these proteins by virus proteases, phosphorylation at two sites known to be involved in PSF translocation or sumoylation. It is dependent on part of PSF, between amino acids 452-606, which is also needed for paraspeckle localization and which is involved in key interactions between PSF, PSPC-1 and NONO. There are few reports on the significance of paraspeckle proteins in virus infection. Our results suggest that we have identified a novel cellular compartment, or a structure induced by virus infection. If this is proved to be required by the virus, then it could be a potential drug target for the development of a new class of antiviral agents against this important group of viruses.