Regulating lysosomal composition and function

The lysosome as a dynamic organelle. (A) Time-lapse of HEK-293T cell expressing GFP-tagged TFEB. Following inhibition of mTORC1, TFEB-GFP massively translocates to the nucleus, where it triggers transcriptional programs leading to lysosomal biogenesis and autophagy (B) Prolonged inhibition of mTORC1 leads to a dramatic expansion of the lysosomal compartment. (C) To determine changes in lysosomal composition resulting from changes in nutrient status and mTORC1 activity, lysosomes are immuno-precipitated and analyzed by quantitative proteomics.

The lysosome as a dynamic organelle. (A) Time-lapse of HEK-293T cell expressing GFP-tagged TFEB. Following inhibition of mTORC1, TFEB-GFP massively translocates to the nucleus, where it triggers transcriptional programs leading to lysosomal biogenesis and autophagy (B) Prolonged inhibition of mTORC1 leads to a dramatic expansion of the lysosomal compartment. (C) To determine changes in lysosomal composition resulting from changes in nutrient status and mTORC1 activity, lysosomes are immuno-precipitated and analyzed by quantitative proteomics.

Our work on amino acid sensing places the lysosome upstream of mTORC1 and of the many anabolic and catabolic processes that mTORC1 controls. For instance, acting via mTORC1, amino acids govern the activity of a family of transcription factors, the MiT/TFE factors, which function as master regulator of lysosomal biogenesis and autophagy.  This lysosome-to-nucleus signaling mechanism, which connects the lysosome’s internal status to catabolic gene expression programs, may be the ‘tip of the iceberg’ of a vast regulatory network for metabolic adaptation. To further explore this network, we will investigate how candidate mTORC1 effectors, which we recently identified, control key properties of lysosomes, including their formation, trafficking and their ability to communicate and exchange nutrients with other organelles.