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

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

Cell (2019-09-21)
Ya-Cheng Liao, Michael S Fernandopulle, Guozhen Wang, Heejun Choi, Ling Hao, Catherine M Drerup, Rajan Patel, Seema Qamar, Jonathon Nixon-Abell, Yi Shen, William Meadows, Michele Vendruscolo, Tuomas P J Knowles, Matthew Nelson, Magdalena A Czekalska, Greta Musteikyte, Mariam A Gachechiladze, Christina A Stephens, H Amalia Pasolli, Lucy R Forrest, Peter St George-Hyslop, Jennifer Lippincott-Schwartz, Michael E Ward
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ANXA11 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Poly(dimethylsiloxane), viscosity 1.0 cSt (25 °C)
Sigma-Aldrich
Nocodazole, ≥99% (TLC), powder
Avanti
18:0-20:4 PI(3,5)P2, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-(1′-myo-inositol-3′,5′-bisphosphate) (ammonium salt), powder