Mechanisms and Regulation of Nuclear mRNA Export

Project Summary In all eukaryotic cells, export of mRNA from the nucleus to the cytoplasm is an essential step in gene expression. As such, mRNA nuclear export is fundamental for all cellular activities and has been linked to various diseases when it is dysregulated, such as in cancer, neurological disorders, and viral infections. Our research focuses on elucidating the mechanisms and regulation of mRNA export under physiological and pathological conditions. Within the nucleus, newly synthesized mRNAs are processed and packaged with proteins to form ribonulceoprotein particles (mRNPs). The core machinery that facilitates the assembly of export-competent mRNPs is the TREX (TRanscription/EXport) complex. Through the enzymatic activity of its ATPase subunit Sub2/DDX39B, TREX facilitates loading of export-specific factors including the export receptor NXF1•NXT1 to form export-competent mRNPs. We have recently elucidated the architecture of the TREX complex and defined key steps of Sub2/DDX39B’s activity. These findings provide a solid foundation for us moving forward to investigate fundamental aspects of mRNA export that remain poorly understood. In this grant period, we aim to identify and structurally characterize the physical and functional interaction network that connects different steps of mRNA export and coordinates the export process with other nuclear events. We envision that these molecular connections spatiotemporally regulate the ATPase- driven mRNP assembly and establish selective export of mature transcripts. The resulting biochemical and structural knowledge will generate hypotheses that we will test at the cellular level. In addition, we aim to investigate how viruses exploit host mRNA export to facilitate their replication. We recently have elucidated the molecular basis for how influenza A virus and SARS-CoV-2 target NXF1•NXT1 to block host gene expression. We will continue to study the various mechanisms that influenza A virus uses to exploit host mRNA export factors. Together, our work will provide mechanistic insights into the mRNA export pathway and may offer novel therapeutic opportunities for viral infections.