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RNA granules hitchhike on lysosomes for long-distance transport, Using annexin A11 as a molecular tether.

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Cell. 2019 Sep 19;179(1):147-164.e20. doi: 10.1016/j.cell.2019.08.050
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RNA granules hitchhike on lysosomes for long-distance transport, Using annexin A11 as a molecular tether. Lippincott-Schwartz Lab
Liao Y, Fernandopulle MS, Wang G, Choi H, Hao L, Drerup CM, Patel R, Qamar S, Nixon-Abell J, Shen Y, Meadows W, Vendruscolo M, Knowles TP, Nelson M, Czekalska MA, Musteikyte G, Gachechiladze MA, Stephens CA, Pasolli HA, Forrest LR, St George-Hyslop P, Lippincott-Schwartz J, Ward ME
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Abstract

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.

PMID: 31539493 [PubMed - indexed for MEDLINE]

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Janelia Authors

Ya-Cheng Liao
Heejun Choi
Jennifer Lippincott-Schwartz
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