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

• Published in: The Journal of cell biology 2015-03, Vol.208 (7), p.913-929
• Main Authors: Somasekharan, Syam Prakash, El-Naggar, Amal, Leprivier, Gabriel, Cheng, Hongwei, Hajee, Shamil, Grunewald, Thomas G P, Zhang, Fan, Ng, Tony, Delattre, Olivier, Evdokimova, Valentina, Wang, Yuzhuo, Gleave, Martin, Sorensen, Poul H
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; Animals; Binding Sites; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cells; Correlation analysis; Cytoplasmic Granules - genetics; DNA Helicases; Humans; Ki-67 Antigen - biosynthesis; Lung Neoplasms - secondary; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Oxidative Stress - genetics; Poly-ADP-Ribose Binding Proteins; Protein Binding; Protein Biosynthesis - genetics; Protein synthesis; Ribonucleic acid; RNA; RNA Helicases; RNA Interference; RNA Recognition Motif Proteins; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering; RNA-Binding Proteins - metabolism; Sarcoma - pathology; Stress, Physiological - genetics; Y-Box-Binding Protein 1 - biosynthesis; Y-Box-Binding Protein 1 - genetics
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201411047

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.