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ZFIN ID: ZDB-PUB-200609-14
RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether
Liao, Y.C., Fernandopulle, M.S., Wang, G., Choi, H., Hao, L., Drerup, C.M., Patel, R., Qamar, S., Nixon-Abell, J., Shen, Y., Meadows, W., Vendruscolo, M., Knowles, T.P.J., Nelson, M., Czekalska, M.A., Musteikyte, G., Gachechiladze, M.A., Stephens, C.A., Pasolli, H.A., Forrest, L.R., St George-Hyslop, P., Lippincott-Schwartz, J., Ward, M.E.
Date: 2019
Source: Cell   179: 147-164.e20 (Journal)
Registered Authors: Drerup, Katie (Catherine)
Keywords: ANXA11, Amyotrophic lateral sclerosis, Local translation, Lysosome, Neurodegeneration, Neuron, Organelles contact, Phase separation, RNA granule, RNA transport
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/metabolism
  • Animals
  • Animals, Genetically Modified
  • Annexins/genetics
  • Annexins/metabolism*
  • Axonal Transport/physiology*
  • Axons/metabolism
  • Cell Line, Tumor
  • Cytoplasmic Granules/metabolism*
  • Female
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Lysosomes/metabolism*
  • Male
  • Mutation
  • Protein Binding
  • RNA/metabolism*
  • Rats/embryology
  • Rats, Sprague-Dawley
  • Transfection
  • Zebrafish
PubMed: 31539493 Full text @ Cell
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.