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Open accessJournal ArticleDOI: 10.1038/S12276-021-00570-6

GSK3B induces autophagy by phosphorylating ULK1

02 Mar 2021-Experimental and Molecular Medicine (Springer Science and Business Media LLC)-Vol. 53, Iss: 3, pp 369-383
Abstract: Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis.

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Topics: MAP1LC3B (67%), Atg1 (66%), Autophagy (60%) ... read more
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8 results found


Open accessJournal ArticleDOI: 10.20517/JCA.2021.13
01 Jan 2021-
Abstract: Introduction Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase and a negative regulator of cardiac hypertrophy. Phosphorylation of GSK-3β at Ser9 negatively regulates its kinase activity. The role of GSK-3β in cardiac aging remains poorly understood. Aim The study aimed to elucidate the role of GSK-3β Ser9 phosphorylation in mediating cardiac aging and the underlying mechanism. Methods and results Phosphorylation of GSK-3β at Ser9 and the levels of β-catenin and Mcl-1 were increased in the mouse heart during aging, suggesting that GSK-3β is inactivated during aging in the heart. Age-induced cardiac hypertrophy, fibrosis, left ventricular dysfunction, and increases in cardiomyocyte apoptosis and senescence were all attenuated in constitutively active GSK-3βS9A knock-in (KI) mice compared to littermate wild type mice. Although autophagy is inhibited in the heart during aging, KI of GSK-3βS9A reversed the age-associated decline in autophagy in the mouse heart. GSK-3β directly phosphorylates Ulk1, a regulator of autophagy, at Ser913, thereby stimulating autophagy in cardiomyocytes. Ulk1Ser913A KI mice exhibited decreased autophagic flux and increased senescence in cardiomyocytes. Conclusion Our results suggest that GSK-3β is inactivated during aging through Ser9 phosphorylation, which in turn plays an important role in mediating cardiac aging. GSK-3β promotes autophagy through phosphorylation of Ulk1 at Ser913, which in turn prevents aging in the heart.

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Topics: Senescence (56%), Autophagy (56%), GSK-3 (54%) ... read more

2 Citations


Open accessJournal ArticleDOI: 10.3389/FNINS.2021.738022
Xi-Yuan Liu1, Rui Lu1, Jing Chen1, Jie Wang1  +4 moreInstitutions (1)
Abstract: Retinal pigment epithelium (RPE) serves critical functions in maintaining retinal homeostasis. An important function of RPE is to degrade the photoreceptor outer segment fragments daily to maintain photoreceptor function and longevity throughout life. An impairment of RPE functions such as metabolic regulation leads to the development of age-related macular degeneration (AMD) and inherited retinal degenerative diseases. As substrate recognition subunit of a ubiquitin ligase complex, suppressor of cytokine signaling 2 (SOCS2) specifically binds to the substrates for ubiquitination and negatively regulates growth hormone signaling. Herein, we explore the role of SOCS2 in the metabolic regulation of autophagy in the RPE cells. SOCS2 knockout mice exhibited the irregular morphological deposits between the RPE and Bruch's membrane. Both in vivo and in vitro experiments showed that RPE cells lacking SOCS2 displayed impaired autophagy, which could be recovered by re-expressing SOCS2. SOCS2 recognizes the ubiquitylated proteins and participates in the formation of autolysosome by binding with autophagy receptors and lysosome-associated membrane protein2 (LAMP-2), thereby regulating the phosphorylation of glycogen synthase kinase 3β (GSK3β) and mammalian target of rapamycin (mTOR) during the autophagy process. Our results imply that SOCS2 participates in ubiquitin-autophagy-lysosomal pathway and enhances autophagy by regulating GSK3β and mTOR. This study provides a potential therapeutic target for AMD.

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Topics: Autolysosome (58%), Autophagy (57%), Photoreceptor outer segment (56%) ... read more

Open accessJournal ArticleDOI: 10.1007/S00702-021-02431-Y
Abstract: Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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Topics: Proteostasis (66%)

Open accessJournal ArticleDOI: 10.1016/J.DRUDIS.2021.11.013
Faqian Bu1, Jifa Zhang1, Wen Shuai1, Jie Liu1  +2 moreInstitutions (1)
Abstract: Autophagy is a multistep degradation pathway involving the lysosome, which supports nutrient reuse and metabolic balance, and has been implicated as a process that regulates cancer genesis and development. Targeting tumors by regulating autophagy has become a therapeutic strategy of interest. Drugs with other indications can have antitumor activity by modulating autophagy, providing a shortcut to developing novel antitumor drugs (i.e., drug repurposing/repositioning), as successfully performed for chloroquine (CQ); an increasing number of repurposed drugs have since advanced into clinical trials. In this review, we describe the application of different drug-repurposing approaches in autophagy for the treatment of cancer and focus on repurposing drugs that target autophagy to treat malignant neoplasms.

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Topics: Drug repositioning (53%), Autophagy (53%), Repurposing (52%)

Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9111639
08 Nov 2021-Biomedicines
Abstract: Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.

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Topics: PI3K/AKT/mTOR pathway (70%), Protein kinase B (59%), Autophagy (50%)

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58 results found


Open accessJournal ArticleDOI: 10.1093/EMBOJ/19.21.5720
Yukiko Kabeya1, Noboru Mizushima1, Noboru Mizushima2, Takashi Ueno3  +10 moreInstitutions (5)
01 Nov 2000-The EMBO Journal
Abstract: Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.

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Topics: Autophagosome membrane (77%), Autophagosome maturation (75%), Autophagosome (72%) ... read more

5,793 Citations


Journal ArticleDOI: 10.1080/15548627.2015.1100356
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
21 Jan 2016-Autophagy
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

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Topics: MAP1LC3B (64%), Chaperone-mediated autophagy (62%), BECN1 (62%) ... read more

4,756 Citations


Open accessJournal ArticleDOI: 10.1038/NCB2152
Abstract: Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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Topics: Atg1 (64%), Autophagy database (64%), Autophagy-Related Protein-1 Homolog (63%) ... read more

4,350 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2010.01.028
05 Feb 2010-Cell
Abstract: Autophagy has been implicated in many physiological and pathological processes. Accordingly, there is a growing scientific need to accurately identify, quantify, and manipulate the process of autophagy. However, as autophagy involves dynamic and complicated processes, it is often analyzed incorrectly. In this Primer, we discuss methods to monitor autophagy and to modulate autophagic activity, with a primary focus on mammalian macroautophagy.

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Topics: Autophagy database (73%), MAP1LC3B (63%), Autolysosome (56%) ... read more

3,613 Citations


Open accessJournal ArticleDOI: 10.1080/15548627.2015.1100356
01 Jan 2011-

3,322 Citations


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