Ezrin defines TSC1 activation at endosomal compartments through EGFR-AKT signaling

Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was deficient in TSC repression by EGF and culminated in translocation of TSC to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function. ### Competing Interest Statement The authors have declared no competing interest. * ### Abbreviations RPE : retinal pigment epithelium POS : photoreceptor outer segment ERM : Ezrin-radix-moesin EZR : Ezrin NHE1 : sodium-hydrogen antiporter 1 EGFR : epidermal growth factor receptor Vsp11 : vacuolar protein sorting 11 PI3K : Phosphoinositide-3-kinase AKT : protein kinase B EGF : epidermal growth factor TSC : Tuberous sclerosis proteins mTOR : mammalian target of rapamycin GTPase : Guanine nucleotide-binding proteins MEF : Mouse Primary Embryonic Fibroblasts LAMP1 : Lysosomal Associated Membrane Protein 1 LC3 : Microtubule-associated proteins 1A/1B light chain 3B CTSB : Cathepsin B HER3 : human epidermal growth factor receptor 3 HER2 : human epidermal growth factor receptor 2 EEA1 : early endosome antigen 1 MAPK : mitogen-activated protein kinase MK2 : Mitogen-activated protein kinase-activated protein kinase 2 ARPE : Retinal Pigment Epithelial Cells.