TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy

Nnah, Israel C.; Wang, Biao; Saqcena, Chaitali; Weber, Gregory F.; Bonder, Edward M.; Bagley, Dustin; Cegli, Rossella De; Napolitano, Gennaro; Medina, Diego L.; Ballabio, Andrea; Dobrowolski, Radoslaw

doi:10.1080/15548627.2018.1511504

Cited by 100 publications

(85 citation statements)

References 45 publications

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“…Recent literature suggests a potential role for TFEB, a key transcription factor involved in lysosomal biogenesis, 49,50 in endocytosis. TFEB controls the expression of key endocytic genes such as Rab5A , Rab7A and CLTA , 51 while cells overexpressing TFEB show enhanced endocytic uptake 51 . It will be exciting to study potential variations in the protein levels or post‐translational modification status of proteins in the TFEB axis at a single cell level under non‐perturbed conditions and assess whether it correlates with heterogeneity of endocytic uptake.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in the endocytic capacity of individual macrophage in a population determines its subsequent phagocytosis, infectivity and subcellular trafficking

Sachdeva

Goel

Sundaramurthy

2020

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Phagocytosis is a complex cellular uptake process involving multiple distinct steps of cargo recognition, uptake, phagosome maturation and eventual phagolysosome resolution. Emerging literature shows that heterogeneity of phagocytosis at multiple steps at a single cell level influences the population outcome. However, the determinants of phagocytic heterogeneity are not clear. Here we show that the variance in the endocytic capacity of individual cells in a macrophage population determines subsequent phagocytic uptake and trafficking. Our results document the extensive heterogeneity in the endocytic uptake of individual macrophages, and show that cells with higher endocytic capacity preferentially phagocytose diverse cargo, including pathogenic Mycobacterium tuberculosis. Interestingly, M. tuberculosis infected cells sustain the higher endocytic capacity following infection. Modulating endocytic capacity by inhibiting endocytosis reduces phagocytic uptake. Differential uptake of M. tuberculosis into cells with different endocytic capacities correlates with the efficiency of phagocytic delivery to lysosomes, thus contributing further to phagocytic as well as mycobacterial heterogeneity. Thus, variance in endocytic capacity is a determinant of generating heterogeneity in phagocytosis at multiple steps.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity in the endocytic capacity of individual macrophage in a population determines its subsequent phagocytosis, infectivity and subcellular trafficking

Sachdeva

Goel

Sundaramurthy

2020

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“…TFEB regulates the expression of genes encoding enzymes involved in sequential steps of autophagic processes such as vesicle (endosome/lysosome) formation and lysosomal enzyme synthesis, among others [20, 21]. Previous studies also showed that TFEB induces expression of a number of core endocytic genes, including the RAB5 gene, and promotes endocytosis during starvation to sustain lysosomal function and autophagy [38]. We found that TFEB is responsible for TGF-β-induced autophagy and that TFEB-driven autophagy induced by TGF-β regulates RAB5A-dependent endocytosis of Itgα5β1 in PC cells.…”

Section: Discussionmentioning

confidence: 99%

TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells

Wang

Zhao

et al. 2019

J Exp Clin Cancer Res

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Background Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-β, provides possible convenience for the progression of PC cells. TGF-β regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-β-mediated autophagy are still poorly understood. Methods Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-β-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-β-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. Results We demonstrated that TGF-β induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-β regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. Conclusions Our findings reveal TFEB-driven autophagy is required for TGF-β induced migration and metastasis of PC cells by promoting endocytosis of Itgα5β1 and focal adhesion disassembly through the TGF-β-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1343-4) contains supplementary material, which is available to authorized users.

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“…Furthermore, mTORC1 regulates the lysosomal function through transcription factor EB (TFEB), which controls the expression of many genes with key roles in lysosomal biogenesis and autophagy mechanism [39]. TFEB-mediated endocytosis induces the assembly of the mTORC1-containing nutrient sensing complex through the formation of endosomes, with further activation of Akt (Akt p-T308) [40].…”

Section: Activity Of Mtor Complexmentioning

confidence: 99%

Targeting mTOR in Acute Lymphoblastic Leukemia

Simioni

Martelli

Zauli

et al. 2019

Cells

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Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.

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TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy

Cited by 100 publications

References 45 publications

Heterogeneity in the endocytic capacity of individual macrophage in a population determines its subsequent phagocytosis, infectivity and subcellular trafficking

Heterogeneity in the endocytic capacity of individual macrophage in a population determines its subsequent phagocytosis, infectivity and subcellular trafficking

TFEB-driven autophagy potentiates TGF-β induced migration in pancreatic cancer cells

Targeting mTOR in Acute Lymphoblastic Leukemia

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