Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Aravinth Kumar Jayabalan; Diane E. Griffin; Anthony K. L. Leung

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/629881 doi: bioRxiv preprint Page 19 SGs and non-membranous condensates are observed in many physiological and pathological contexts in virus infection, cancers and neurodegenerative diseases [1, [12] [13] [14] . Preclinical studies showed that PARP inhibitors reduce the number of non-membranous pathological aggregates in models of neurodegenerative disease [26, 30, 76] and PARG knockout flies revealed progressive neurodegeneration with observable cytoplasmic aggregates [77] . Consistent with these findings, our data showed that expression of wild-type nsP3, but not an ADP-ribosylhydrolase-deficient nsP3 mutant, can reduce the number of SG-like aggregates formed upon expression of the FUS protein mutant R495X, which is linked to an aggressive form of ALS. These data altogether suggest possible therapeutic options for reduction of non-membranous protein aggregates by lowering PAR levels, either through inhibiting PARP or increasing the ADP-ribosylhydrolase activity. Viruses: CHIKV 181/25 WT and mutant strains were prepared as described previously [69] . Viral stocks were grown in BHK21 cells and assayed by plaque formation in Vero cells.