Stress granules are dispensable for mRNA stabilization during cellular stress

TLDR

Cellular stress suppresses protein synthesis and drives bulk mRNA into stress granules. The study investigates whether mRNA stabilization during stress requires stress granule formation. FRAP and photo‑conversion experiments reveal that TIA1, TIAR, and G3BP1 only transiently associate with stress granules. Knocking down TIA1, TIAR, and G3BP1 abolishes visible stress granules, yet mRNA stabilization remains because stable IGF2BP1/HUR‑containing mRNPs are recruited to granules by these proteins, showing that aggregation into visible granules is dispensable for preventing mRNA degradation.

Abstract

During cellular stress, protein synthesis is severely reduced and bulk mRNA is recruited to stress granules (SGs). Previously, we showed that the SG-recruited IGF2 mRNA-binding protein 1 (IGF2BP1) interferes with target mRNA degradation during cellular stress. Whether this requires the formation of SGs remained elusive. Here, we demonstrate that the sustained inhibition of visible SGs requires the concomitant knockdown of TIA1, TIAR and G3BP1. FRAP and photo-conversion studies, however, indicate that these proteins only transiently associate with SGs. This suggests that instead of forming a rigid scaffold for mRNP recruitment, TIA proteins and G3BP1 promote SG-formation by constantly replenishing mRNPs. In contrast, RNA-binding proteins like IGF2BP1 or HUR, which are dispensable for SG-assembly, are stably associated with SGs and the IGF2BP1/HUR-G3BP1 association is increased during stress. The depletion of IGF2BP1 enhances the degradation of target mRNAs irrespective of inhibiting SG-formation, whereas the turnover of bulk mRNA remains unaffected when SG-formation is impaired. Together these findings indicate that the stabilization of mRNAs during cellular stress is facilitated by the formation of stable mRNPs, which are recruited to SGs by TIA proteins and/or G3BP1. Importantly, however, the aggregation of mRNPs to visible SGs is dispensable for preventing mRNA degradation.