GCN2 upregulates autophagy in response to short-term deprivation of a single essential amino acid

Maurin, Anne‐Catherine; Parry, Laurent; B'Chir, Wafa; Carraro, Valérie; Coudy-Gandilhon, Cécile; Chaouki, Ghita; Chaveroux, Cédric; Mordier, Sylvie; Martinie, Brigitte Gaillard; Reinhardt, Vanessa; Jousse, Céline; Bruhat, Alain; Codogno, Patrice; Avérous, Julien; Fafournoux, Pierre

doi:10.1080/27694127.2022.2049045

Cited by 10 publications

(5 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 J ), suggesting the auxiliary interaction between Depdc5 and RagC is necessary for efficient initiation of autophagy under nutrient-deprived conditions. At late time points, autophagy is eventually initiated in the mutant cell line, suggesting parallel pathways, such as GCN2, may kick in and act independently of mTORC1 ( 46 , 47 ). These mTORC1-independent pathways activate autophagy and may feed back, causing a loss in the mTORC1-dependent markers, such as S6K1 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells

Doxsey,

Tettoni,

Egri

et al. 2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells

Doxsey,

Tettoni,

Egri

et al. 2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Skeletal muscle from patients with low BCAAs levels and cirrhosis reveals reduced the activation of downstream targets of mTOR1 (p70S6K, S6, 4EBP1) but elevated levels of the intracellular amino acid sensor General Control of Nutrition Derepressed 2 (GCN2) [37]. This suggests activation of autophagic pathways, as GCN2 is known to elevate autophagic activity in response to short-term essential amino acid deprivation, particularly leucine, in an mTOR1 dependent manner [52].…”

Section: Interplay Of Bcaas Mtor Signaling Ammonia and Mitochondrial ...mentioning

confidence: 99%

Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver

Trillos-Almanza,

Martinez-Aguilar,

Arroyave-Ospina

et al. 2024

Muscles

View full text Add to dashboard Cite

This comprehensive review focuses on the dynamics of branched-chain amino acids (BCAAs) metabolism and its clinical implications in chronic liver disease, with emphasis on the emerging concept of muscle–liver crosstalk. BCAAs, indispensable for protein synthesis and metabolic pathways, undergo unique tissue-specific processing in skeletal muscle and liver. The liver, responsible for amino acid metabolism, plays a distinctive role in sensing BCAAs catabolism, influencing glucose regulation and contributing to the systemic metabolism of BCAAs. Within the context of chronic liver disease, compromised liver metabolism becomes evident through amino acid abnormalities, particularly in the decrease of the Fischer ratio (BCAAs/aromatic amino acids concentrations in plasma). This reduction becomes important in assessing the severity of liver dysfunction due to its associations with adverse outcomes, including increased mortality and complications related to the liver disease. BCAAs supplementation, as explored in this review, emerges as a promising avenue, displaying positive effects on skeletal muscle mass, strength, and overall nutritional status in cirrhosis management. Understanding this interplay offers insights into therapeutic strategies for chronic liver diseases, exploring the way for precision interventions in clinical practice.

show abstract

“…Considering that autophagy is an adaptive cellular mechanism operating under conditions of nutrient starvation [101], it is reasonable to propose that GCN2 may play a significant role in activating autophagy during amino acid deprivation. Indeed, it has been demonstrated that GCN2 kinase is capable of initiating autophagy by suppressing the mTORC1 complex [102][103][104]. Notably, GCN2-mediated short-term activation of autophagy requires both the phosphorylation of eIF2α and the suppression of the mTORC1 complex, but it does not necessitate the activation of ATF4 [103].…”

Section: Isr and Autophagymentioning

confidence: 99%

“…Indeed, it has been demonstrated that GCN2 kinase is capable of initiating autophagy by suppressing the mTORC1 complex [102][103][104]. Notably, GCN2-mediated short-term activation of autophagy requires both the phosphorylation of eIF2α and the suppression of the mTORC1 complex, but it does not necessitate the activation of ATF4 [103]. It can be hypothesized that GCN2 activates the «early» autophagy by mobilizing the basal pool of existing autophagy proteins and their mRNAs that are already present in a cell.…”

Section: Isr and Autophagymentioning

confidence: 99%

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence

Kalinin,

Zubkova,

Menshikov

2023

IJMS

View full text Add to dashboard Cite

Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.

show abstract

GCN2 upregulates autophagy in response to short-term deprivation of a single essential amino acid

Cited by 10 publications

References 78 publications

Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells

Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells

Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence

Contact Info

Product

Resources

About