Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival

Saini, Neetu; Naaz, Afsana; Metur, Shree Padma; Gahlot, Pinki; Walvekar, Adhish; Dutta, Anupam; Davathamizhan, Umamaheswari; Sarin, Apurva; Laxman, Sunil

doi:10.26508/lsa.202201663

Cited by 10 publications

(6 citation statements)

References 64 publications

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“…Among the important metabolites for our model, methionine uptake by the SLC43A2 transporter has recently been reported to be crucial for Treg viability upon IL-2 deprivation. 35 We found an inverse correlation between methionine levels at baseline and the increase in Treg number. We can hypothesize that with less circulating methionine,…”

Section: Promising Prediction Of Treg Increase From Baseline Metabolomementioning

confidence: 59%

Pharmacometabolomics applied to low‐dose interleukin‐2 treatment in amyotrophic lateral sclerosis

Alarcan,

Bruno,

Emond

et al. 2024

Annals of the New York Academy of Sciences

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Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low‐dose (ld) interleukin‐2 (IL‐2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld‐IL‐2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL‐2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld‐IL‐2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

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Section: Promising Prediction Of Treg Increase From Baseline Metabolomementioning

confidence: 59%

Pharmacometabolomics applied to low‐dose interleukin‐2 treatment in amyotrophic lateral sclerosis

Alarcan,

Bruno,

Emond

et al. 2024

Annals of the New York Academy of Sciences

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“…3 More recently, methionine uptake has been shown to crucial to the activation and proliferation of T cells. [36][37][38] However, dietary methionine restriction was also shown to delay age-related changes in T cell subsets in mice, drawing a more complex picture of the immune effects of the treatment. 39 Finally, reducing methionine in the diet has been reported to promote anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Characterization of methionine dependence in melanoma cells

Garg,

Morehead,

Bird

et al. 2024

Mol. Omics

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“…Interestingly, lymphocytes are the only non-cancer cell type reported to be methionine dependent (3). More recently, methionine uptake has been shown to crucial to the activation and proliferation of T cells (33)(34)(35). However, dietary methionine restriction was also shown to delay age-related changes in T cell subsets in mice, drawing a more complex picture of the immune effects of the treatment (36).…”

Section: Discussionmentioning

confidence: 99%

Characterization of methionine dependence in melanoma cells

Garg

Morehead

Bird

et al. 2023

Preprint

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Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood. We do know that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but triggers different outcomes in methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and immune functions in the cellular response to methionine stress in melanoma.

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Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival

Cited by 10 publications

References 64 publications

Pharmacometabolomics applied to low‐dose interleukin‐2 treatment in amyotrophic lateral sclerosis

Pharmacometabolomics applied to low‐dose interleukin‐2 treatment in amyotrophic lateral sclerosis

Characterization of methionine dependence in melanoma cells

Characterization of methionine dependence in melanoma cells

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