Specific amino acids regulate Sestrin2 mRNA and protein levels in an ATF4-dependent manner in C2C12 myocytes

Sawa, Ran; Ohnishi, Ayaka; Ohno, Maya; Nagata, Maika; Wake, Ikumi; Okimura, Yasuhiko

doi:10.1016/j.bbagen.2022.130174

Cited by 4 publications

(1 citation statement)

References 39 publications

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“…Additionally, our data support the literature to show that glutamine, arginine, and cysteine deprivations are accompanied with oxidative and energetic stress [ 36 , 37 , 38 , 39 , 40 ]. However, we showed that besides canonical nutritional stress, conducted through GCN2-ATF4 signaling pathway [ 20 , 41 , 42 ], oxidative stress was contributing to the Sestrin2 induction. Group 2 is a prime example of the negative correlation between Sestrin2 expression and cellular survival dependent on the cellular metabolic background.…”

Section: Discussionmentioning

confidence: 99%

Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1

Blagojevic

Almouhanna

Poschet

et al. 2022

Cells

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Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming.

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