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MTORC1 feedback to AKT modulates MiT/TFE-driven lysosomal biogenesis and EGFR degradation

ABSTRACT: MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. Some tumors bypass this regulatory circuit via genetic alterations that drive MiT/TFE expression and activity; however, the mechanisms by which cells with intact or constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we find that epidermal Tsc1 deletion results in a wavy hair phenotype due to increased EGFR degradation. Unexpectedly, constitutive mTORC1 activation increases lysosomal content via up-regulated expression and activity of MiT/TFEs, while genetic or prolonged pharmacologic mTORC1 inactivation has the reverse effect. This paradoxical up-regulation of lysosomal biogenesis by mTORC1 is mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE proteasomal degradation. These data suggest that oncogenic feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE124754 | GEO | 2020/04/14

REPOSITORIES: GEO

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mTORC1 feedback to AKT modulates MiT/TFE-driven lysosomal biogenesis and EGFR degradation

Project description:mTORC1 feedback to AKT modulates MiT/TFE-driven lysosomal biogenesis and EGFR degradation

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Project description:The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.

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Transcriptional regulation of ER-phagy by MiT/TFE factors controls chondrocyte differentiation and bone formation

Project description:Lysosomal-autophagic degradation of Endoplasmic Reticulum via autophagy (ER-phagy) is emerging as critical regulator of ER homeostasis and function. However, the molecular mechanisms governing ER-phagy are still unknown. Working in chondrocytes, we found that ER-phagy and lysosome biogenesis are co-activated by FGF signaling during hypertrophic differentiation, a mandatory step for bone formation. FGF induced ER-phagy trough IRS1-dependent inhibition of the insulin signaling and activation of MiT/TFE transcription factors, master regulators of lysosome biogenesis. MiT/TFE promoted ER-phagy through the induction of the ER-phagy receptor FAM134B. Notably, the activation of ER-phagy promotes chondrocytes differentiation and secretion of factors required for cartilage replacement by bone. Consistently, medaka fish knock-down for FAM134B have impaired ossification of cranial bones. Thus, ER-phagy is a transcriptionally regulated process that participates to cell differentiation during development.

2020-07-15 | PXD015331 | Pride

MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B

Project description:Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of ER homeostasis and function1. The selective incorporation of ER fragments into nascent autophagosomes is facilitated by ER resident proteins, ER-phagy receptors, that bind the autophagosomal LC3 protein via the cytosolic LC3 interacting domain (LIR) (REF). However, the molecular mechanisms that regulate ER-phagy in response to cellular needs are still largely unknown. We found that the MiT/TFE transcription factors - master regulators of lysosomal biogenesis and autophagy2- control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. This pathway is robustly activated in chondrocytes by FGF signaling, a critical regulator of chondrocyte differentiation3. FGF triggers TFEB/TFE3-mediated ER-phagy through JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS-1) protein and inhibition of the insulin signaling. FAM134B knock-down impairs cartilage growth and mineralization in medaka fish, suggesting a physiological role for this process during skeletal growth. Notably, we showed that the TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. Thus, this study identifies MiT/TFE-factors as key transcriptional activators of ER-phagy in response to both metabolic and developmental cues.

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RNA-Seq Samples of siTFE3 in 8988T PDA Cell Line to Investigate Transcriptional Control of the Autophagy-Lysosome System

Project description:The activation of cellular quality control pathways to maintain metabolic homeostasis and mitigate diverse cellular stresses is emerging as a critical growth and survival mechanism in many cancers. Autophagy, a highly conserved cellular self-degradative process, is a key player in the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA). However, the regulatory circuits that activate autophagy, and how they enable reprogramming of PDA cell metabolism are unknown. We now show that autophagy regulation in PDA occurs as part of a broader program that coordinates activation of lysosome biogenesis, function and nutrient scavenging, through constitutive activation of the MiT/TFE family of bHLH transcription factors. In PDA cells, the MiT/TFE proteins - MITF, TFE3 and TFEB - override a regulatory mechanism that controls their nuclear translocation, resulting in their constitutive activation. By orchestrating the expression of a coherent network of genes that induce high levels of lysosomal catabolic function, the MiT/TFE factors are required for proliferation and tumorigenicity of PDA cells. Importantly, unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular AA pools in PDA. This AA flux is part of a program that is essential for metabolic homeostasis and bioenergetics of PDA but not for their non-transformed counterparts. These results identify the MiT/TFE transcription factors as master regulators of the autophagy-lysosomal system in PDA and demonstrate a central role of the autophagosome-lysosome compartment in maintaining tumor cell metabolism through alternative amino acid acquisition and utilization. Examination of mRNA levels in pancreatic ductal adenocarcinoma (PDA) cell line 8988T after treatment with siRNA for control or TFE3

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RNA-Seq Samples of siTFE3 in 8988T PDA Cell Line to Investigate Transcriptional Control of the Autophagy-Lysosome System

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ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation

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Project description:In an attempt to elucidate the role of MiT/TFE families in the iron-mediated phenotypic changes of macrophages, we performed DNA microarray analysis using ferric chloride-stimulated RAW264 cells transfected with Tfe3/Tfeb or GFP. A number of genes upregulated by ferric chloride treatment in siGFP-transfected RAW264 cells were decreased in siTfe3/Tfeb-transfected cells, suggesting MiT/TFE families are involved in phenotypic changes of macrophages induced by iron.

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Gene expression regulated by transcription factor MiT in Drosophila

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2015-08-01 | E-GEOD-58416 | biostudies-arrayexpress

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