Long-distance RNA transport plays a critical role in cells by enabling local protein translation at metabolically-active sites distant from the nucleus. This ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a novel mechanism for RNA transport, in which RNA granules indirectly “hitchhike” on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as an adaptor between RNA granules and lysosomes. ANXA11 possesses an Nterminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. ALS-associated mutations in ANXA11 decrease long-range transport of RNA granules in neurons by disrupting their docking onto lysosomes. Thus, ANXA11 enables neuronal RNA transport via lysosomal hitchhiking of RNA granules, performing a critical cellular function that is disrupted in ALS.
Liao, Ya-Cheng and Fernandopulle, Michael and Wang, Guozhen and Choi, Heejun and Hao, Ling and Drerup, Catherine M. and Qamar, Seema and Nixon-Abell, Jonathon and Shen, Yi and Meadows, William and Vendruscolo, Michele and Knowles, Tuomas and Nelson, Matthew and Czekalska, Magda and Musteikyte, Greta and Patel, Rajan and Stephens, Christina and Pasolli, Amalia and Forrest, Lucy and George-Hyslop, Peter St and Lippincott-Schwartz, Jennifer and Ward, Michael E., RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether (January 9, 2019). Available at SSRN: https://ssrn.com/abstract=3312723 or http://dx.doi.org/10.2139/ssrn.3312723
This version of the paper has not been formally peer reviewed.