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bioRxiv · 10.1101/629881

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Jayabalan, A. K.·Griffin, D. E.·Leung, A. K. L.
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Abstract

Formation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1. We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADP-ribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions.

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Jayabalan, A. K., Griffin, D. E., Leung, A. K. L.. 2019-06-20. Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation. https://doi.org/10.1101/629881

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