Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

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

For alphaviruses, SGs are first induced in the early stage of infection and subsequently disassembled [32, 34] . It was previously proposed that the disassembly is mediated through the sequestration of the essential SG component G3BP1/2 by associating with the C-terminal HVD domain of nsP3 [35, 36, 41] . Though we confirmed the association between nsP3 and G3BP1, our data show that the expression of the HVD domain alone does not suppress SG formation. It is therefore unlikely that nsP3 causes SG disassembly through HVD sequestration of G3BP1/2 alone. Yet, G3BP1/2 and its association with the nsP3 HVD are required for CHIKV replication [40, 62] . We note, however, that the HVD is composed of low-complexity regions [39] , which are increasingly appreciated for their role in mediating the assembly of non-membranous structures [6] [7] [8] . Here, we instead propose a model of how nsP3 mediates SG disassembly, wherein the C-terminal HVD promotes the association between nsP3 and SG proteins so that the N-terminal MD can act locally to remove ADP-ribosylation in SGs. As an increasing amount of nsP3 is expressed over the course of infection, a higher level of ADP-All rights reserved. No reuse allowed without permission.