Rapidly evolving PARP proteins act as both positive and negative regulators of the antiviral response

Abstract

Abstract Viral manipulation of cellular post-translational modifications (PTMs) can be key to their survival and replication. One understudied PTM that has been implicated in the antiviral response is ADP-ribosylation. To manipulate this modification, several viral families encode for a macrodomain capable of binding and removing ADP-ribosylation. Importantly, disruption of this function can lead to reduction in pathogenesis or increases in sensitivity to the host interferon response. While the family of host proteins capable of catalyzing ADP-ribosylation, known as PARPs, is large, a subset show multiple signs of rapid evolution, including gene duplication and loss as well as recurrent sequence changes. Focusing in on these genes, we have found that the long isoform of PARP13 is acting directly to inhibit Sindbis virus, a member of the macrodomain-containing alphavirus family. The full antiviral activity requires the presence of the PARP domain in addition to proper localization. In contrast to this, the short isoform acts as a negative regulator of the interferon response by binding and degrading Interferon mRNAs. The balance between antiviral and proviral functions creates a novel dynamic that is potentially more resistant to viral antagonism. We are now exploring the role of ADP-ribosylation in modulating these two phenotypes.