Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK

Jin, Hong; Du, Charles H.; Wang, Chong‐Zhi; Yuan, Chun‐Su; Du, Wei

doi:10.1038/s41419-019-1548-7

Cited by 26 publications

(14 citation statements)

References 56 publications

(54 reference statements)

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“…The naturally occurring resveratrol inhibits hepatic lipogenesis through Sesn2 induction (Jin et al, 2013), thus keeping fatty liver in check. Nelfinavir/bortezomib (Bruning et al, 2013) and protopanaxadiol (PPD) (Jin et al, 2019) are known to induce Sesn2 through protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)/ cyclic AMP-dependent transcriptional factor (ATF) 4 activation upon ER stress. Albeit the increasing therapeutic potential of allosteric modulation of Sestrin2 is promising, the unexpected side effects should be thoroughly examined by animal studies and human clinical trials.…”

Section: Introduction Of Sestrinsmentioning

confidence: 99%

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Fay

Cyuzuzo

et al. 2020

Front. Cell Dev. Biol.

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Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.

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Section: Introduction Of Sestrinsmentioning

confidence: 99%

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Fay

Cyuzuzo

et al. 2020

Front. Cell Dev. Biol.

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“…It is a common phenomenon that PERK and GCN2 kinases simultaneously regulate the same substrate (Hamanaka et al, 2005;Krishnamoorthy et al, 2008;You et al, 2018;Jin et al, 2019). We used PERK or GCN2 inhibitor to treat DEFs and found that both inhibitors can attenuate eIF2α phosphorylation, related to the redundancy or even compensation of the two kinases' functions (Donnelly et al, 2013;You et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Duck Hepatitis A Virus Type 1 Induces eIF2α Phosphorylation-Dependent Cellular Translation Shutoff via PERK/GCN2

et al. 2021

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Duck hepatitis A virus type 1 (DHAV-1) is one of the most deadly pathogens that endanger the duck industry. Most viruses usually turn off host translation after infection to facilitate viral replication and translation. For the first time report to our knowledge, DHAV-1 can induce eIF2α phosphorylation and inhibit cellular translation in duck embryo fibroblasts (DEFs). Moreover, the activity of DHAV-1 in the cells caused obvious eIF2α phosphorylation, which has nothing to do with the viral protein. Subsequently, we screened two kinases (PERK and GCN2) that affect eIF2α phosphorylation through inhibitors and shRNA. Notably, the role of GCN2 in other picornaviruses has not been reported. In addition, when the phosphorylation of eIF2α induced by DHAV-1 is inhibited, the translation efficiency of DEFs restores to a normal level, indicating that DHAV-1 induced cellular translation shutoff is dependent on eIF2α phosphorylation.

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“…Inhibition of GCN2 reduces LC3 accumulation when arginine is downregulated due to IFN-γ treatment in bovine mammary epithelial cells (BMECs) [ 41 ]. In HCT116 cells, GCN2 functions downstream of protopanaxadiol (PPD) to promote autophagy by upregulating the expression of Sestrin2 [ 42 ]. Interestingly, Sestrin2 interferes with translocation of mTORC1 to lysosomes [ 43 ], thereby inhibiting mTORC1 activity.…”

Section: Sensing Mechanisms Of Amino Acid Regulation Autophagymentioning

confidence: 99%

Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

Liu

et al. 2021

IJMS

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Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

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Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK

Cited by 26 publications

References 56 publications

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Duck Hepatitis A Virus Type 1 Induces eIF2α Phosphorylation-Dependent Cellular Translation Shutoff via PERK/GCN2

Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

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