mTORC1 as the main gateway to autophagy

Rabanal-Ruíz, Yoana; Otten, Elsje G.; Korolchuk, Viktor I.

doi:10.1042/ebc20170027

Cited by 373 publications

(248 citation statements)

References 183 publications

(268 reference statements)

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“…In the absence of activating stimulation, autophagy is induced by dissociation of mTORC1 complex from the ULK1 complex, thereby relieving the inhibition of ULK1, which is then responsible for its phosphorylation and phosphorylation of FIP200, Atg13, and Raptor. ULK1 is then able to activate this PI3K complex and promote autophagosome synthesis . Upon activation, mTORC1 promotes anabolic processes through phosphorylation of its eukaryotic translation initiation factor 4E binding protein and downstream effectors ribosomal protein S6 kinase, thereby inducing cell proliferation and growth .…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

et al. 2019

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Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well‐organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post‐transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA‐based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy‐related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.

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Section: Introductionmentioning

confidence: 99%

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

et al. 2019

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“…Autophagy is suppressed by mTORC1 while it is enhanced by AMPK and is thus engaged under conditions of nutrient limitation and serves to ensure a supply of essential metabolites. We suggest several excellent recent reviews on this subject, but do not specifically discuss metabolic control of autophagy. Here, we focus on the regulation of endocytic membrane traffic by metabolic sensors including AMPK, mTORC1 and HIF1, and by metabolically sensitive posttranslational modifications, with emphasis on mammalian studies, supplemented by selected examples of conserved regulation from yeast and other organisms.…”

Section: Introductionmentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…Autophagy plays important roles in the physiology and pathogenesis of several kidney diseases, such as ischemia-reperfusion or nephrotoxins induced acute kidney injury (AKI), 1-3,34,35 diabetic nephropathy, 5 and glomerular disease. 27,37 Our results indicated that the levels of p-4EBP1 and p-P70S6K proteins were higher in the VEGF-C depletion groups than in the control siRNA treatment groups. 24 After baflomycin A1 treatment, a lower fold-change in the LC3-II level in VEGF-C knockdown group was observed compared with the negative control group, suggesting VEGF-C depletion inhibited the autophagic degradation, thereby dysregulated autophagy.…”

Section: Discussionmentioning

confidence: 68%

“…27 So, we examined the effects of VEGF-C and NRP-2 knockdown on mTORC1 signalling axis by western blot. mTOR is evolutionarily highly conserved and forms two different functional protein complexes, mTORC1 and mTORC2.…”

Section: Effect Of Knockdown Vegf-c and Nrp-2 On The Expression Ofmentioning

confidence: 99%

Roles for VEGF‐C/NRP–2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation

Chang

Yang

Zhang

et al. 2019

Cell Biochemistry & Function

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Vascular endothelial growth factor C (VEGF‐C) is an angiogenic and lymphangiogenic growth factor. Recent research has revealed the role for VEGF‐C in regulating autophagy by interacting with a nontyrosine kinase receptor, neuropilin‐2 (NRP–2). However, whether VEGF‐C participates in regulating cell survival and autophagy in renal proximal tubular cells is unknown. To address this question, we employed a cell modal of serum deprivation to verify the role of VEGF‐C and its receptor NRP–2 in regulating cell survival and autophagy in NRK52E cell lines. The results show that VEGF‐C rescued the loss of cell viability induced by serum deprivation in a concentration‐dependent manner. Furthermore, endogenous VEGF‐C was knocked down in NRK52E cells by using specific small‐interfering RNAs (siRNA), cells were more sensitive to serum deprivation–induced cell death. A similar increase in cell death rate was observed following NRP–2 depletion in serum‐starved NRK52E cells. Autophagy activity in serum‐starved NRK52E cells was confirmed by western blot analysis of microtubule‐associated protein‐1 chain 3 (LC3), immunofluorescence staining of endogenous LC3, and the formation of autophagosomes by electron microscopy. VEGF‐C or NRP–2 depletion further increased LC3 expression induced by serum deprivation, suggesting that VEGF‐C and NRP–2 were involved in controlling autophagy in NRK52E cells. We further performed autophagic flux experiments to identify that VEGF‐C promotes the activation of autophagy in serum‐starved NRK52E cells. Together, these results suggest for the first time that VEGF‐C/NRP–2 axis promotes survival and autophagy in NRK52E cells under serum deprivation condition. Significance of the study More researchers had focused on the regulation of autophagy in kidney disease. The effect of VEGF‐C on cell death and autophagy in renal epithelial cells has not been examined. We first identified the VEGF‐C as a regulator of cell survival and autophagy in NRK52E cell lines. And VEGF‐C/NRP–2 may mediate autophagy by regulating the phosphorylation of 4EBP1 and P70S6K. VEGF‐C treatment may be identified as a therapeutic target in renal injury repair due to its capacity to promote tubular cell survival in the future.

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mTORC1 as the main gateway to autophagy

Cited by 373 publications

References 183 publications

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

Energetic adaptations: Metabolic control of endocytic membrane traffic

Roles for VEGF‐C/NRP–2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation

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