Progranulin mediates endolysosomal recruitment of the RNP-associated protein ANXA11
Ya-Cheng Liao1, Michael Fernandopulle2, Ling Hao2, Rajan Patel2, Jennifer Lippincott-Schwartz1, Michael E Ward2* 1Howard Hughes Medical Institute, Janelia Research Campus, Ashurn, VA 2National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD *Corresponding Author
GRN gene mutations cause loss of expression of the intra-endolysosomal protein progranulin, lysosomal dysfunction, and frontotemporal dementia (FTD) with pathologic aggregates of the RNA-binding protein TDP-43. Using proximity-labeling proteomics in iPSC-derived neurons, we found that GRN-KO neurons had diminished endolysosomal recruitment of ANXA11, a nucleocytosolic protein of unknown function recently implicated in familial ALS. FLIM-FRET and photoconversion microscopy studies showed that ANXA11 is dynamically recruited to endolysosomal membranes in a GRN-dependent manner. In addition to C-terminal annexin repeats, which interact with membrane lipids and calcium, ANXA11 has an intrinsically disordered prion-like domain in its N-terminus. Live cell FLIP microscopy revealed a stable pool of ANXA11 that co-localized with stress granule markers, including TDP-43. Light-activated phase-separation of ANXA11-cry2 fusion proteins caused bulk redistribution of ANXA11 to endolysosomes, including ANXA11 droplets that co-localized with stress-granule markers. Taken together, our findings suggest that the unique combination of membrane-binding and intrinsically disordered-domains of ANXA11 may serve as a molecular bridge between endolysosomal membranes and phase-separated ribonuclear protein complexes, and that loss of GRN-mediated ANXA11 activity may play an important role in FTD pathogenesis.
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