ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF MTORC1 ACTIVITY BY MIT/TFE TRANSCRIPTION FACTORS

The mechanistic Target Of Rapamycin Complex 1 (mTORC1) regulates cellular biosynthetic pathways in response to variations in nutrient availability. Activation of mTORC1 is mediated by Rag GTPases, that act as heterodimers and promote mTORC1 recruitment to the lysosome. Many studies have clarified the post-translational control of mTORC1, but little is known about its transcriptional regulation. Our study demonstrates that TFEB, TFE3 and MITF, members of the MiT/TFE family of transcription factors and master regulators of lysosomal and melanosomal biogenesis and autophagy, are nutrient-sensitive transcriptional activators of mTORC1 signaling. During starvation they induce the expression of the RagD gene and this enhances mTORC1 recruitment to the lysosome and its reactivation when nutrients become available. Thus, in periods of nutrient deprivation, this mechanism allows the cell to rapidly reactivate anabolic pathways and turn off catabolism when nutrient levels are restored. Furthermore this mechanism plays an important role in cancer growth. Up-regulation of the MiT/TFE genes in renal cell carcinoma and melanoma is associated to RagD-induced mTORC1 activation, causing cell hyperproliferation and cancer progression.