VPg unlinkase/TDP2 in cardiovirus infected cells: Re-localization and proteolytic cleavage

Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5′ end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV. We found that EMCV yields are reduced in the absence of TDP2. We observed a decrease in viral protein accumulation and viral RNA replication in the absence of TDP2. In contrast to enterovirus infections, we found that TDP2 is modified at peak times of EMCV infection. This finding suggests a unique mechanism for cardioviruses to regulate TDP2 activity during infection. •We hypothesized that picornaviruses use TDP2/VPg unlinkase to mark viral RNAs for specific uses during picornavirus replication.•Data from the current study showed that TDP2 re-localizes from the nucleus to the cytoplasm of EMCV infected cells.•EMCV yields are significantly reduced during infection of mouse embryonic fibroblasts genetically ablated for TDP2.•TDP2 is cleaved during EMCV infection, providing a new example of host protein modification during picornavirus infections.