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Cell. 2019 Sep 19;179(1):147-164.e20. doi: 10.1016/j.cell.2019.08.050.

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

Author information

1
HHMI Janelia Research Campus, Ashburn, VA, USA.
2
NINDS, NIH, Bethesda, MD, USA.
3
Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK.
4
NICHD, NIH, Bethesda, MD, USA.
5
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
6
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK; Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK.
7
Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine (Division of Neurology), University of Toronto and University Health Network, Toronto, Ontario M5S 3H2, Canada.
8
HHMI Janelia Research Campus, Ashburn, VA, USA. Electronic address: lippincottschwartzj@janelia.hhmi.org.
9
NINDS, NIH, Bethesda, MD, USA. Electronic address: wardme@nih.gov.

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.

KEYWORDS:

ANXA11; Amyotrophic lateral sclerosis; Local translation; Lysosome; Neurodegeneration; Neuron; Organelles contact; Phase separation; RNA granule; RNA transport

PMID:
31539493
DOI:
10.1016/j.cell.2019.08.050
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