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The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.
Pubmed ID: 22343943 RIS Download
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Generate, archive, and distribute world-wide up to 12.000 conditional mutations across the mouse genome in mouse embryonic stem (ES) cells and Establish a limited number of mouse mutants from this resource. EUCOMM contributes the largest fraction of conditionally trapped and targeted genes in mouse C57BL/6N embryonic stem (ES) cells to the IKMC. EUCOMM vectors, mutant ES cells and mutant mice are distributed worldwide, enabling functional genomics research in a standardized and cost-effective manner by a much wider biomedical research community than has been possible previously. EUCOMM mutant ES cells and vectors can be obtained from the European Mouse Mutant Cell Repository (EuMMCR). EUCOMM mutant mice are archived and distributed by the European Mouse Mutant Archive (EMMA). Mutagenesis Strategies * Conditional gene trapping - random approach for expressed genes * Conditional targeted trapping - directed approach, used for expressed genes * Conditional gene targeting - directed approach, used for non-expressed genes
View all literature mentionsInstitution of higher education in the United States. Private Ivy League research university in Cambridge, Massachusetts.
View all literature mentionsCenter that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine function of every gene in mouse genome. These mice will be preserved in repositories and made available to scientific community representing valuable resource for basic scientific research as well as generating new models for human diseases.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
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