G3BP isoforms differentially affect stress granule assembly and gene expression during cellular stress

Mol Biol Cell. 2024 Nov 1;35(11):ar140. doi: 10.1091/mbc.E24-02-0062. Epub 2024 Oct 2.

Abstract

Stress granules (SGs) are macromolecular assemblies that form under cellular stress. Formation of these membraneless organelles is driven by the condensation of RNA and RNA-binding proteins such as G3BPs. G3BPs form SGs following stress-induced translational arrest. Three G3BP paralogues (G3BP1, G3BP2A, and G3BP2B) have been identified in vertebrates. However, the contribution of different G3BP paralogues to SG formation and gene expression changes is incompletely understood. Here, we probed the functions of G3BPs by identifying important residues for SG assembly at their N-terminal domain such as V11. This conserved amino acid is required for formation of the G3BP-Caprin-1 complex, hence promoting SG assembly. Total RNA sequencing and ribosome profiling revealed that a G3BPV11A mutant leads to changes in mRNA levels and ribosome engagement during the integrated stress response (ISR). Moreover, we found that G3BP2B preferentially forms SGs and promotes changes in mRNA expression under endoplasmic reticulum (ER) stress. Furthermore, our work is a resource for researchers to study gene expression changes under cellular stress. Together, this work suggests that perturbing protein-protein interactions mediated by G3BPs affect SG assembly and gene expression during the ISR, and such functions are differentially regulated by G3BP paralogues under ER stress.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cytoplasmic Granules / metabolism
  • DNA Helicases* / genetics
  • DNA Helicases* / metabolism
  • Endoplasmic Reticulum Stress / physiology
  • Gene Expression / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Poly-ADP-Ribose Binding Proteins* / genetics
  • Poly-ADP-Ribose Binding Proteins* / metabolism
  • Protein Isoforms* / metabolism
  • RNA Helicases* / genetics
  • RNA Helicases* / metabolism
  • RNA Recognition Motif Proteins* / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Stress Granules* / metabolism
  • Stress, Physiological

Substances

  • RNA Recognition Motif Proteins
  • Poly-ADP-Ribose Binding Proteins
  • G3BP1 protein, human
  • RNA Helicases
  • G3BP2 protein, human
  • DNA Helicases
  • RNA-Binding Proteins
  • Protein Isoforms
  • CAPRIN1 protein, human
  • Carrier Proteins
  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins