Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity

Aravinth Kumar Jayabalan, Srivathsan Adivarahan, Aakash Koppula, Rachy Abraham, Mona Batish, Daniel Zenklusen, Diane Griffin, Anthony K.L. Leung

Research output: Contribution to journalArticlepeer-review

Abstract

While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The alphavirus virulence factor nonstructural protein 3 (nsP3) suppresses the formation of stress granules (SGs)-a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-binding proteins. Expression of ADP-ribosylhydrolase-deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-binding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during alphavirus infection.

Original languageEnglish (US)
Article numbere2021719118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number6
DOIs
StatePublished - Feb 9 2021

Keywords

  • ADP-ribosylation
  • Alphavirus
  • Biomolecular condensates
  • Macrodomain
  • Stress granules

ASJC Scopus subject areas

  • General

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