BioProject

MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. More...

MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. Some tumors bypass this regulatory circuit via genetic alterations that drive MiT/TFE expression and activity; however, the mechanisms by which cells with intact or constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we find that epidermal Tsc1 deletion results in a wavy hair phenotype due to increased EGFR degradation. Unexpectedly, constitutive mTORC1 activation increases lysosomal content via up-regulated expression and activity of MiT/TFEs, while genetic or prolonged pharmacologic mTORC1 inactivation has the reverse effect. This paradoxical up-regulation of lysosomal biogenesis by mTORC1 is mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE proteasomal degradation. These data suggest that oncogenic feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling. Overall design: We performed microarray-based differential expression analysis of E18.5 epidermis from wild-type (3 biological replicates) and Rptor cKO (3 biological replicates) epidermal RNA samples and performed Gene Set Enrichment Analysis, GSEA to evaluate whether a lysosomal gene signature panel (consisting of 360 lysosomal gene transcripts from the Mouse Lysosome Gene Database (mLGDB; http://lysosome.unipg.it/mouse.php) was significantly negatively enriched in Rptor cKO epidermis. Less...