YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

TLDR

Cell stress inhibits global protein synthesis and induces stress granules that sequester mRNAs; Y-box binding protein 1 localizes to these granules, but its role in SG biology was previously unclear. YB‑1 directly binds the 5′UTR of G3BP1 mRNA, activating its translation and thereby regulating G3BP1 levels essential for stress granule assembly; loss of YB‑1 or G3BP1 in sarcoma cells diminishes SG formation, reduces tumor invasion, and abolishes lung metastasis, linking YB‑1‑mediated SG biogenesis to cancer progression.

Abstract

Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression.