Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.

Bioinformatics Unit Life Sciences Core Facilities Weizmann Institute of Science Rehovot Israel

Department of Biological Sciences University of South Carolina Columbia SC USA

Department of Pharmaceutical Chemistry University of California San Francisco San Francisco CA USA

Department of Veterinary Resources Weizmann Institute of Science Rehovot Israel

Departments of Biomolecular Sciences and Molecular Neuroscience Weizmann Institute of Science Rehovot Israel

Departments of Psychiatry and Neurology Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles CA USA

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic

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