A lysosome-to-nucleus signaling mechanism senses and regulates the lysosome via mTOR and TFEB. The lysosome plays a key role in cellular homeostasis by controlling cellular clearance and energy production in response to environmental cues. The mechanisms mediating lysosomal adaptation are largely unknown. This study shows that the transcription factor TFEB, a master regulator of lysosomal biogenesis, colocalizes with the master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, mTORC1 phosphorylates TFEB, inhibiting its activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. The transcriptional response of lysosomal and autophagic genes to lysosomal dysfunction or mTORC1 inhibition is suppressed in TFEB-deficient cells. The Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These findings indicate that the lysosome senses its content and regulates its own biogenesis through a lysosome-to-nucleus signaling mechanism involving TFEB and mTOR. The study also shows that mTORC1 regulates TFEB subcellular localization via phosphorylation of S142. The lysosome regulates gene expression via TFEB, as demonstrated by the transcriptional response of lysosomal and autophagic genes in primary hepatocytes. The study highlights the role of the lysosome as a key signaling center, with TFEB acting as a sensor and effector of lysosomal function. The findings suggest that TFEB is a key mediator of the transcriptional response to lysosomal stress and that the lysosome-to-nucleus signaling mechanism is essential for maintaining cellular homeostasis. The study provides new insights into the regulation of lysosomal function and the role of TFEB in cellular homeostasis.A lysosome-to-nucleus signaling mechanism senses and regulates the lysosome via mTOR and TFEB. The lysosome plays a key role in cellular homeostasis by controlling cellular clearance and energy production in response to environmental cues. The mechanisms mediating lysosomal adaptation are largely unknown. This study shows that the transcription factor TFEB, a master regulator of lysosomal biogenesis, colocalizes with the master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, mTORC1 phosphorylates TFEB, inhibiting its activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. The transcriptional response of lysosomal and autophagic genes to lysosomal dysfunction or mTORC1 inhibition is suppressed in TFEB-deficient cells. The Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These findings indicate that the lysosome senses its content and regulates its own biogenesis through a lysosome-to-nucleus signaling mechanism involving TFEB and mTOR. The study also shows that mTORC1 regulates TFEB subcellular localization via phosphorylation of S142. The lysosome regulates gene expression via TFEB, as demonstrated by the transcriptional response of lysosomal and autophagic genes in primary hepatocytes. The study highlights the role of the lysosome as a key signaling center, with TFEB acting as a sensor and effector of lysosomal function. The findings suggest that TFEB is a key mediator of the transcriptional response to lysosomal stress and that the lysosome-to-nucleus signaling mechanism is essential for maintaining cellular homeostasis. The study provides new insights into the regulation of lysosomal function and the role of TFEB in cellular homeostasis.