Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation

Kim, Sung‐Hoon; Choi, Jung‐Hyun; Wang, Peng; Go, Christopher D.; Hesketh, Geoffrey G.; Gingras, Anne‐Claude; Jafarnejad, Seyed Mehdi; Sonenberg, Nahum

doi:10.1016/j.molcel.2020.11.036

Cited by 34 publications

(32 citation statements)

References 44 publications

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“…When nutrient availability is limited, mTORC1 is inactivated, in part through AMPK activation 15, 16 . Interestingly, while the intermediate sensitive and resistant cell lines showed decreased mTORC1 activity under glucose deprivation (0 mM glucose), as indicated by the changes in phosphorylation pattern of S6K (Thr389) and 4EBP1 (Thr37/46 and Ser65) as described elsewhere 29 , the sensitive cell lines (U2OS and U251MG) maintained high mTORC1 activity, as indicated by the increased molecular weight of phosphorylation of S6K and 4EBP1 as described 29 . These data indicate that sensitive cell lines maintained high mTOR and low AMPK activities under glucose deprivation, whereas resistant cell lines increased AMPK and reduced mTOR activities to adapt to the metabolically challenging conditions.…”

Section: Resultsmentioning

confidence: 70%

A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

Itahana

Ong

et al. 2021

Preprint

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Accelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the selective therapeutic targeting of this vulnerability has yielded mixed results owing to the different sensitivities of each cancer type to glucose removal and lack of insight into the underlying mechanisms of glucose deprivation-induced cell death. Here, we screened multiple cell lines to determine their sensitivities to glucose deprivation and found that the cell lines most sensitive to glucose deprivation failed to activate AMPK, a major regulator of metabolic adaptation, resulting in metabolic catastrophe. Notably, glucose deprivation-induced AMPK dysregulation and rapid cell death were observed only in cancer cell lines with high expression of cystine/glutamate antiporter xCT. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. We found that cystine uptake and glutamate export through xCT under glucose deprivation contributes to rapid NADPH depletion, leading to the collapse of the redox system, which subsequently inactivates AMPK by inhibitory oxidation and phosphorylation. This AMPK dysregulation caused a failure of metabolic switch to fatty acid oxidation upon glucose deprivation, resulting in mitochondrial dysfunction and cell death. Taken together, these findings suggest a novel cross-talk between the metabolic and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation and provide a rationale for targeting glucose metabolism in these cancer cells.

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Section: Resultsmentioning

confidence: 70%

A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

Itahana

Ong

et al. 2021

Preprint

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“…6 ). The molecules involved in sensing different amino acids are found on the plasma membrane ( 55 ) and in the cytosol ( 23 , 38 , 56 ) and organelles, including mitochondria and lysosome ( 57 , 58 ). Presumably, oligodendrocyte lineage cells could employ multiple mechanisms to sense the availability of different amino acids.…”

Section: Discussionmentioning

confidence: 99%

GATOR2 complex–mediated amino acid signaling regulates brain myelination

Yang

Ren

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type–dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.

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“…This might be attributable to its impact on PolI-mediated transcription and subsequently nucleolar hyperplasia. mTOR is at the core of the translational regulation by converging signaling transduction from a variety of nutrients and growth factors (13,14,(72)(73)(74)(75)(76). Activation of mTOR signaling has been involved in the pathogenesis of cardiac hypertrophy; however, cardiac-specific ablation of raptor impairs adaptive hypertrophy, but causes heart failure in mice (15).…”

Section: Discussionmentioning

confidence: 99%

NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy

Guo

Zheng

Sun

et al. 2021

Front. Cardiovasc. Med.

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Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocytes (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas, immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome-related pathways are remarkably enriched in the down-regulated genes. Although Nap1l5-mediated gene regulation is correlated with PRC2 and PRC1, Nap1l5 does not directly alter the levels of global histone methylations at K4, K9, K27 or K36. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to promote protein synthesis in cardiomyocyte hypertrophy. This is attributable to a direct regulation of nucleolus hypertrophy and subsequent ribosome assembly. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.

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Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation

Cited by 34 publications

References 44 publications

A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

GATOR2 complex–mediated amino acid signaling regulates brain myelination

NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy

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