Long-distance RNA transport enables local protein synthesis at metabolicallyactive
sites distant from the nucleus. This process ensures an appropriate spatial
organization of proteins, vital to polarized cells such as neurons. Here, we
present a mechanism for RNA transport in which RNA granules “hitchhike” on
moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and
unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an
RNA granule-associated phosphoinositide-binding protein, acts as a molecular
tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal
low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS) mutations impair RNA granule transport in neurons by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS
