Abstract
Lysosomes serve as dynamic regulators of cell and organismal physiology by integrating the degradation of macromolecules with receptor and nutrient signaling. Previous studies have established that activation of the transcription factor EB (TFEB) and transcription factor E3 (TFE3) induces the expression of lysosomal genes and proteins in signaling-inactive starved cells, that is, under conditions when activity of the master regulator of nutrient-sensing signaling mechanistic target of rapamycin complex 1 is repressed. How lysosome biogenesis is triggered in signaling-active cells is incompletely understood. Here, we identify a role for calcium release from the lumen of the endoplasmic reticulum in the control of lysosome biogenesis that is independent of mechanistic target of rapamycin complex 1. We show using functional imaging that calcium efflux from endoplasmic reticulum stores induced by inositol triphosphate accumulation upon depletion of inositol polyphosphate-5-phosphatase A, an inositol 5-phosphatase downregulated in cancer and defective in spinocerebellar ataxia, or receptor-mediated phospholipase C activation leads to the induction of lysosome biogenesis. This mechanism involves calcineurin and the nuclear translocation and elevated transcriptional activity of TFEB/TFE3. Our findings reveal a crucial function for inositol polyphosphate-5-phosphatase A–mediated triphosphate hydrolysis in the control of lysosome biogenesis via TFEB/TFE3, thereby contributing to our understanding how cells are able to maintain their lysosome content under conditions of active receptor and nutrient signaling.
Highlights
Late endosomes and lysosomes coordinate the degradative turnover of macromolecules, e.g. proteins, lipids, and defective organelles, with cell metabolism [1,2,3,4] by responding to intracellular cues and extracellular signals such as insulin or growth factors [5]
In the present study we combine genetic and pharmacological manipulations with light and electron microscopy to show that IP3induced calcium efflux from endoplasmic reticulum (ER) stores in the absence of the inositol-triphosphate [IP3]specific inositol 5-phosphatase INPP5A [16,17], an enzyme downregulated in cancer and defective in spinocerebellar ataxia, triggers lysosome biogenesis via calcineurin-mediated activation of transcription factor EB (TFEB) and TFE3 independent of cellular nutrient status monitored by mTORC1
Given that INPP5A acts on IP3 receptors in the ER [21], we considered the possibility that the observed accumulation of lysosomes upon depletion of INPP5A might be an indirect consequence of ER stress, which in turn could target the ER for autophagic turnover in lysosomes
Summary
Late endosomes and lysosomes coordinate the degradative turnover of macromolecules, e.g. proteins, lipids, and defective organelles, with cell metabolism [1,2,3,4] by responding to intracellular cues and extracellular signals such as insulin or growth factors [5]. While TFEB inositol 5-phosphatase downregulated in cancer and its close relative TFE3 are kept cytosolically and defective in spinocerebellar ataxia, or inactive under steady-state conditions, a variety receptor-mediated phospholipase C activation of stimuli including lysosome [8,9] and osmotic leads to the induction of lysosome biogenesis. In the present study we combine genetic and pharmacological manipulations with light and electron microscopy to show that IP3induced calcium efflux from ER stores in the absence of the inositol-triphosphate [IP3]specific inositol 5-phosphatase INPP5A [16,17], an enzyme downregulated in cancer and defective in spinocerebellar ataxia, triggers lysosome biogenesis via calcineurin-mediated activation of TFEB and TFE3 independent of cellular nutrient status monitored by mTORC1
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