Simon Bullock: "Shedding light on cytoplasmic mRNA transport mechanisms"

Subcellular mRNA localisation is used in many cell types to control where proteins operate. Whilst it has long been recognised that cytoskeletal motors play a central role in mRNP trafficking, it is unclear how mRNAs are recruited to motors and how motor activity is regulated in these assemblies. I will present our efforts to address these questions using two experimental models: early Drosophila development and human cancer cells. High-resolution cryo-EM structures of the Drosophila RNA adaptor Egalitarian (Egl) complexed with the dynein motor activator Bicaudal-D (BicD) and three double-stranded RNA targets reveal the basis of mRNA recognition in this system. The results of single-molecule resolution in vitro motility assays show that two RNA stem-loops are required to activate dynein motility, a finding rationalised by Alphafold-assisted modelling of RNA-protein complexes. I will also present evidence that the RNA-binding proteins FXR1 and FXR2 are long-sought-after adaptors between dynein and mRNAs in human cells. Like Drosophila Egl, FXR1 and FXR2 associate directly with a BicD family member and enable its dynein-activating functions. Collectively, our work reveals similar organisational principles of mRNA transport complexes in divergent eukaryotic cell types, with the RNA cargo determined by the specificity of interchangeable RNA-binding proteins.