RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome

TLDR

Stress granules are ubiquitous, non‑membrane‑bound assemblies of protein and RNA that form when translation initiation is inhibited, regulate gene expression, and are implicated in cancer and neurodegenerative disease, making their assembly mechanisms a key focus of study. The authors propose a summative model of stress granule assembly that incorporates trans‑RNA–RNA interactions and can be generalized to other ribonucleoprotein granules. They demonstrate that RNA–RNA interactions drive stress granule assembly, that pathogenic dipeptides increase RNA assembly propensity, and that RNAs are inherently assembly‑prone and must be tightly regulated.

Abstract

Significance Stress granules, which are ubiquitous, non–membrane-bound assemblies of protein and RNA, form when translation initiation is inhibited, contribute to the regulation of gene expression, and are implicated in the pathologies of cancer and neurodegenerative disease. Understanding the mechanisms of stress granule assembly is crucial to gaining greater insight into their biological function and pathological misregulation. We provide evidence that RNA–RNA interactions contribute to the assembly of stress granules. Furthermore, we show that pathogenic dipeptides increase the propensity of RNA to assemble. Together, this argues that RNAs are assembly prone and must be carefully regulated. A summative model of stress granule assembly, which includes trans -RNA–RNA interactions, can be extended to other ribonucleoprotein granules in the cell.