Abstract
SummaryLong-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.
Highlights
Many proteins within cells are translated locally rather than trafficked from their site of synthesis to their final destination
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 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in amyotrophic lateral sclerosis (ALS)
Summary
Many proteins within cells are translated locally rather than trafficked from their site of synthesis to their final destination. RNA granules have long been observed to traffic within neuronal axons and dendrites (Knowles et al, 1996; Gopal et al, 2017). While their transport requires both microtubules and motor proteins, how membraneless RNA granules are tethered to transport machinery remains incompletely understood (Clark et al 2007; Davidovic et al 2007; Dictenberg et al 2008; Dienstbier et al 2009; Dix et al 2013; Gaspar et al 2017; Gagnon et al 2013)
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