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Lysosomal limiting membrane lipids regulate mTORC1 signaling and lysosome positioning: Basal cholesterol levels, PI(3,5)P2, and PI(3)P are activators of mTORC1. PI(3,5)P2is solely required for the mTORC1 non-canonical substrate TFEB while PI(3)P regulates mTORC1 canonical substrates such as S6K and 4E-BP as well as lysosome positioning via KIF16b and FYCO1. MTMRs, PI4K2A, and PI3KC2B mediate the starvation response by producing PI(4)P and PI(3,4)P2, mTORC1 inhibition, perinuclear clustering of lysosomes, and increased cholesterol transfer. In contrast, VPS34 and Sac1 are driving feeding responses. Sac1 is a ER resident proteins and relies on ORP proteins to transfer PI(4)P to the ER where Sac1 can dephosphorylate PI(4)Pin cis. Phosphoinositide transfer proteins (PITPs) shuttle PI from the ER to endolysosomes. Feedback mechanisms in this regulatory network are mTORC1-mediated inhibition of PI4K2A, VPS34 activation by mTORC1, and PI(4)P-dependent recruitment of MTMRs. Which 3’ and 4’ phosphoinositide phosphatases metabolize PI(3,5)P2and PI(3,4)P2on lysosomes is currently unclear.

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