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      Gastrodin induces lysosomal biogenesis and autophagy to prevent the formation of foam cells via AMPK‐FoxO1‐TFEB signalling axis

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          Abstract

          Abnormal accumulation of lipids and massive deposition of foam cells is a primary event in the pathogenesis of atherosclerosis. Recent studies have demonstrated that autophagy and lysosomal function of atherosclerotic macrophages are impaired, which exacerbates the accumulation of lipid in macrophages and formation of foam cells. Gastrodin, a major active component of Gastrodia elata Bl., has exerted a protective effect on nervous system, but the effect of gastrodin on atherosclerotic vascular disease remains unknown. We aimed to evaluate the effect of gastrodin on autophagy and lysosomal function of foam cells and explored the mechanism underlying gastrodin's effect on the formation of foam cells. In an in vitro foam cell model constructed by incubating macrophages with oxygenized low‐density lipoproteins (ox‐LDL), our results showed that lysosomal function and autophagy of foam cells were compromised. Gastrodin restored lysosomal function and autophagic activity via the induction of lysosomal biogenesis and autophagy. The restoration of lysosomal function and autophagic activity enhanced cholesterol efflux from macrophages, therefore, reducing lipid accumulation and preventing formation of foam cells. AMP‐activated protein kinase (AMPK) was activated by gastrodin to promote phosphorylation and nuclear translocation of forkhead box O1 (FoxO1), subsequently resulting in increased transcription factor EB (TFEB) expression. TFEB was activated by gastrodin to promote lysosomal biogenesis and autophagy. Our study revealed that the effect of gastrodin on foam cell formation and that induction of lysosomal biogenesis and autophagy of foam cells through AMPK‐FoxO1‐TFEB signalling axis may be a novel therapeutic target of atherosclerosis.

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          AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

          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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            TFEB links autophagy to lysosomal biogenesis.

            Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.
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              A gene network regulating lysosomal biogenesis and function.

              Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induced lysosomal biogenesis and increased the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington's disease. Thus, a genetic program controls lysosomal biogenesis and function, providing a potential therapeutic target to enhance cellular clearing in lysosomal storage disorders and neurodegenerative diseases.
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                Author and article information

                Contributors
                sunlinkm@126.com
                ludi20040609@126.com
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                10 May 2021
                June 2021
                : 25
                : 12 ( doiID: 10.1111/jcmm.v25.12 )
                : 5769-5781
                Affiliations
                [ 1 ] Science and Technology Achievement Incubation Center Kunming Medical University Kunming China
                [ 2 ] Department of Anatomy Faculty of Basic Medical Sciences Kunming Medical University Kunming China
                [ 3 ] Department of Cardiology the Second Affiliated Hospital Kunming Medical University Kunming China
                Author notes
                [*] [* ] Correspondence

                Di Lu, Science and Technology Achievement Incubation Center, Kunming Medical University, NO.1168 Chunrong Road West, Kunming, China.

                Email: ludi20040609@ 123456126.com

                Lin Sun, Department of Cardiology, the Second Affiliated Hospital, Kunming Medical University, NO. 374 Dianmian Road, Kunming, China.

                Email: sunlinkm@ 123456126.com

                Author information
                https://orcid.org/0000-0001-5716-8451
                Article
                JCMM16600
                10.1111/jcmm.16600
                8184689
                33973365
                42a49928-73cf-4a84-b12a-9c2d4b687513
                © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 March 2021
                : 06 January 2021
                : 19 April 2021
                Page count
                Figures: 7, Tables: 0, Pages: 13, Words: 7919
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 31760292
                Award ID: 81760087
                Award ID: 81560050
                Funded by: Department of Science and Technology of Yunnan Province of China
                Award ID: 2017FA035
                Award ID: 2017FE467
                Award ID: 2019ZF011‐2
                Funded by: Department of Science and Technology of Yunnan Province of China
                Award ID: 2017FE468
                Award ID: 202001AT070105
                Funded by: Department of Science and Technology of Yunnan Province of China
                Award ID: 2019FE001
                Funded by: Major Program of Kunming Science and Technology Innovation Center
                Award ID: 2019‐1‐N‐25318000003568
                Funded by: Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (IRTSTYN), China Postdoctoral Science Foundation
                Award ID: 2018M633424
                Funded by: Yunnan Postdoctoral Science Foundation, Yunnan Province postdoctoral oriented training program, and the Hundred‐Talent Program of Kunming Medical University
                Award ID: 60118090113
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                June 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:07.06.2021

                Molecular medicine
                autophagy,foam cells,gastrodin,lysosomal function,lysosome biogenesis
                Molecular medicine
                autophagy, foam cells, gastrodin, lysosomal function, lysosome biogenesis

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