NEDDylation stabilizes eIF3g and eIF3i during stress

Stress granules, or SGs, are cytoplasmic structures that form when translation stalls, trapping stalled complexes and related proteins. The roles of individual initiation factors within SGs and their release during stress resolution are still unclear. By analyzing a NEDD8-conjugated proteome alongside a previously identified NEDD8 interactome and existing databases on RNA granules, researchers discovered that eIF3g and eIF3i are NEDDylated components in SGs.

The presence of NEDDylation in eIF3g and eIF3i complexes is evident at baseline and diminishes under arsenite-induced stress. Notably, only the full-length eIF3g is recruited to SGs, while a truncated version lacking the RRM domain hinders SG formation despite not concentrating within these structures. Disrupting the NEDD8 pathway—through inhibition of NAE with MLN4924, depletion of NEDD8 pathway components, or activation of the deNEDDylase NEDP1—speeds up the loss of eIF3g and eIF3i during stress.

This suggests that NEDDylation stabilizes a degradation-resistant pool of eIF3g and eIF3i, enabling their proper localization to SGs. This connection between NEDD8 signaling and initiation factor proteostasis may be crucial for translating protein synthesis recovery during stress resolution.