RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Long-distance RNA transport plays a critical role in cells by enabling local protein translation at metabolically-active sites distant from the nucleus. This ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a novel mechanism for RNA transport, in which RNA granules indirectly “hitchhike” on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as an adaptor between RNA granules and lysosomes. ANXA11 possesses an Nterminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. ALS-associated mutations in ANXA11 decrease long-range transport of RNA granules in neurons by disrupting their docking onto lysosomes. Thus, ANXA11 enables neuronal RNA transport via lysosomal hitchhiking of RNA granules, performing a critical cellular function that is disrupted in ALS.