FXR proteins and BICD2 cooperate to promote dynein-mediated RNP transport and stress granule assembly

Intracellular trafficking of ribonucleoprotein particles (RNPs) is a widespread strategy for regulating gene expression, yet how this process is orchestrated in mammalian systems remains unclear. Here, we show that Bicaudal D2 (BICD2), a partner of the microtubule motor dynein, is complexed with RNA-binding proteins (RBPs) in human cells. We also reveal that two of these RBPs - the Fragile X-related proteins FXR1 and FXR2 - bind directly to BICD2 and recruit mRNAs to dynein. Surprisingly, given its conventional designation as a cargo adaptor, BICD2 is not needed for dynein to interact with FXR1 and FXR2. Using in vitro reconstitution, we demonstrate that BICD2 instead activates dynein motility in concert with the FXR proteins. These data support a model in which BICD2 is recruited to pre-existing RNP-motor complexes, where it is licensed by the FXR proteins to activate processive movement. We further provide evidence that FXR proteins, BICD2 and dynein cooperate to promote rapid formation of stress granules, large RNPs that form in the cytoplasm in response to cellular insults. Collectively, our work reveals molecular mechanisms underlying RNP transport and stress granule assembly in human cells and indicates that cargo recruitment and motor activation are separable steps in dynein-mediated transport.