DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress

Summary In eukaryotes, regulation of mRNA translation initiation greatly impacts gene expression, and is critical for cellular stress responses. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in 5‘ UTR scanning and start codon decoding in non-stressed and stressed cells is still elusive. Here we show that DDX3X engages with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex, simultaneously acting to promote or suppress translation of select mRNAs in non-stressed conditions, and switches this regulation in opposite directions in acute ER stress. We find distinct DDX3X binding patterns of differentially regulated mRNAs, which lead us to identify N4-acetylation of cytidines surrounding the start codon as an accompanying feature of mRNAs subject to DDX3X-mediated selective dual regulation. Our findings illuminate the role of DDX3X in stress response and highlight a novel connection between an RNA helicase and a post-transcriptional modification in regulating mRNA translation.