A novel role of EWSR1 protein in RNA translation regulation

The Ewing Sarcoma breakpoint region 1 protein (EWSR1) is a member of the FET (FUS, EWSR1, and TAF15) family of proteins, implicated in several aspects of cell biology and found mutated in multiple diseases. Primarily, EWSR1 attracted broad attention as one of the most susceptible genes to breakage/translocation, originally identified because of the t(11;22)(q24;q12) chromosomal translocation, characteristic of Ewing sarcoma. Interestingly, EWSR1 contains two functional domains: a potent N-terminal transcriptional activation domain (NTD), with several conserved serine-tyrosine-glycine-glutamine (SYGQ) repeats, revealed in the context of oncogenic EWSR1-fusions, and a C-terminal domain (CTD), modulating different aspects of RNA processing. Although extensive studies on oncogenes generated in Ewing sarcoma, only limited information was available about the function of EWSR1 protein itself. It is only until recently, that various EWSR1 cellular functions have been revealed, but the exact mechanisms are not yet understood. Importantly, EWSR1 was identified as a multifunctional protein implicated in transcriptional and post-transcriptional mechanisms. Considering its implication in post-transcriptional regulation, we decided to investigate whether EWSR1 might also be involved in mRNA translation.

In this work, we highlight that EWSR1 is a repressor of translation of a specific subset of mRNA and decipher the molecular mechanisms underlying this function. We show that this new activity is mediated by the RGG2-ZnF-RGG3 region of the CTD. Interestingly, we evidence that this region is also implicated in the association of EWSR1 with the 40S ribosomal subunit. Therefore, we conclude that EWSR1-mediated repression of translation is correlated with its ability to associate with the 40S. Importantly, we show that EWSR1 activity in the repression of translation is crucial for the regulation of lipid homeostasis. This function is primordial to maintain normal endoplasmic reticulum (ER) shape and function, but also to properly activate the unfolded protein response (UPRER). In the future, these findings might lead to novel therapeutic opportunities for diseases in which EWSR1 is implicated, especially that the CTD region, which is responsible for the translational regulation, was reported to be mutated in several diseases or totally lost in oncogenic EWSR1-ETS fusions, such as Ewing sarcoma. Verily, unraveling EWSR1 at the molecular level is not only important for understanding gene expression, but is also of medical relevance, as aberrant function of the protein is the basis of many human diseases.