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

Summary

Long-distance RNA transport enables local protein synthesis at metabolically-active 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)-associated mutations in ANXA11 impair RNA granule transport 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.

Graphical Abstract

Highlights

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  RNA granules “hitchhike” on motile lysosomes during long-distance transport

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  ANXA11 binds to RNA and lysosomes via phase separating and membrane binding domains

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  ANXA11 tethers RNA granules to lysosomes and is required for axonal RNA transport

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  ALS-associated ANXA11 mutations impair its tethering function and RNA transport

Abstract

Annexin A11, a protein with mutations associated with ALS, tethers membraneless RNA granules to actively-transported lysosomes via its intrinsic membrane-binding and phase separating properties, enabling efficient transport of RNA to distal regions of the neuron.