EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis
Zahrat El Oula Hassoun, Loic Ongena, Lionel Condé, Bartimée Galvan, Grégory Fettweis, Michelle Lion, Romuald Soin, Jonathan Bruyr, Florence Lemaitre, Marc Thiry, Emeline Mariavelle, Margaux Claes, Arnaud Blomme, Gerben Menschaert, Jonas Dehairs, Véronique Kruys, Cyril Gueydan, Tina M O’grady, Johannes V Swinnen, Sylvain de Breyne, Théophile Ohlmann, Jean-Claude Twizere, Yvette Habraken, Franck DequiedtAbstract
FET family proteins (FUS, EWSR1, and TAF15) have garnered significant attention due to their involvement in oncogenic fusions and mutations in various cancers and neurodegenerative disorders. Although these highly conserved RNA-binding proteins are widely described as multifunctional regulators of gene expression, their precise molecular functions remain incompletely understood. Here, we uncover a previously unrecognized role for EWSR1 as a selective translational repressor in cancer cells. EWSR1 specifically targets mRNAs involved in lipid metabolism and endoplasmic reticulum (ER) homeostasis. Loss of EWSR1 disrupts ER morphology and impairs activation of the unfolded protein response of the ER (UPRER). Mechanistically, EWSR1 represses translation upon association with target mRNAs, and its conserved region spanning two arginine–glycine–glycine (RGG) boxes contributes to association with the 40S ribosomal subunit. These findings define a novel role for EWSR1 in post-transcriptional gene regulation and suggest that perturbations in its translational activity may underlie the pathogenesis of FET-associated diseases.