EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis
8 affiliations
- 1Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège , 4000 Liege ,
- 2CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, INSERM U1111, Université Claude Bernard Lyon 1 , CNRS UMR5308, ENS de Lyon, F-69007 Lyon ,
- 3Laboratoire de Biologie Moléculaire du Gène, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles (ULB) , 6041 Gosselies ,
- 4Laboratory of Cell and Tissue Biology, GIGA Institute, University of Liège , 4000 Liege ,
- 5Laboratory of Metabolic Regulation, GIGA Institute, University of Liège , 4000 Liege ,
- 6Biobix, Laboratory of Bioinformatics and Computational Genomics, Ghent University , 9000 Ghent ,
- 7Laboratory of Lipid Metabolism and Cancer, Department of Oncology, Leuven Cancer Institute and Leuven Institute for Single Cell Omics (LISCO) , KU Leuven, Leuven B-3000 ,
- 8Laboratory of Viral Interactomes Networks, GIGA Institute, University of Liège , 4000 Liege ,
Abstract
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.
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BibTeX
@article{hassoun2026ewsr1,
title = {{EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis}},
author = {Zahrat El Oula Hassoun and Loic Ongena and Lionel Condé and Bartimée Galvan and Grégory Fettweis and Michelle Lion and Romuald Soin and Jonathan Bruyr and Florence Lemaitre and Marc Thiry and Emeline Mariavelle and Margaux Claes and Arnaud Blomme and Gerben Menschaert and Jonas Dehairs and Véronique Kruys and Cyril Gueydan and Tina M O’grady and Johannes V Swinnen and Sylvain de Breyne and Théophile Ohlmann and Jean-Claude Twizere and Yvette Habraken and Franck Dequiedt},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag1022},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1022/9004256},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis
AU - Zahrat El Oula Hassoun
AU - Loic Ongena
AU - Lionel Condé
AU - Bartimée Galvan
AU - Grégory Fettweis
AU - Michelle Lion
AU - Romuald Soin
AU - Jonathan Bruyr
AU - Florence Lemaitre
AU - Marc Thiry
AU - Emeline Mariavelle
AU - Margaux Claes
AU - Arnaud Blomme
AU - Gerben Menschaert
AU - Jonas Dehairs
AU - Véronique Kruys
AU - Cyril Gueydan
AU - Tina M O’grady
AU - Johannes V Swinnen
AU - Sylvain de Breyne
AU - Théophile Ohlmann
AU - Jean-Claude Twizere
AU - Yvette Habraken
AU - Franck Dequiedt
PY - 2026
DA - 2026/10/01
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1022
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1022/9004256
AB - 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.
SN - 0305-1048
SN - 1362-4962
ER -