Cellular signallingJul 9, 2026

NSUN2 links sugar and one-carbon metabolism to mTORC1 signaling controlled by Rag GTPases

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 10, 2026

Abstract

In AMPK-deficient human cells, glucose refeeding rapidly reactivated mTORC1.

NSUN2 was identified as a glucose-associated factor that is crucial for mTORC1 activation.
Loss of NSUN2 significantly reduced glucose-induced mTORC1 activation, while its re-expression restored this activation.
Genetic analysis indicated that NSUN2 acts upstream of the lysosomal Rag module, as active Rag GTPases could bypass the effects of NSUN2 deficiency.
The acute signaling function of NSUN2 was found to largely depend on a specific nutrient-responsive motif rather than its catalytic activity.
Methionine adenosyltransferase 2A (MAT2A), a SAM-producing enzyme, was identified as a glucose-responsive partner of NSUN2, with MAT2A knockout leading to similar signaling defects.
Transcriptomics linked NSUN2 to various glucose-responsive programs related to cellular processes like proteostasis and stress adaptation.

Simplified

How glucose and one‑carbon metabolism converge on Rag GTPase-dependent mechanistic target of rapamycin complex 1 (mTORC1) remains poorly defined, particularly in the absence of AMP-activated protein kinase (AMPK). This study mapped an AMPK-independent glucose-response pathway in human cells using CRISPR editing, rescue assays, proteomics, thermal stability analysis, and RNA sequencing. In AMPK-deficient human cells, glucose refeeding rapidly reactivated mTORC1, and proteomics of mTORC1-associated complexes identified NSUN2 as a glucose-associated factor. NSUN2 loss markedly reduced glucose-induced mTORC1 activation, whereas re-expression restored it. Genetic analyses placed NSUN2 upstream of the lysosomal Rag module because constitutively active Rag GTPases bypassed NSUN2 deficiency. Structure-function studies showed that the acute signaling role of NSUN2 was largely independent of its catalytic cysteines, but required an N-terminal nutrient-responsive motif and a predicted S-adenosylmethionine (SAM)-responsive segment. SAM increased the thermal stability of wild-type NSUN2, and proteomics and Immunoprecipitation identified methionine adenosyltransferase 2 A (MAT2A), a SAM-producing enzyme, as a glucose-responsive NSUN2 partner. MAT2A knockout reproduced the signaling defect. Transcriptomics further linked NSUN2 to glucose-responsive programs in proteostasis, secretion, and stress adaptation. These results identify NSUN2 as a noncanonical signaling factor that couples glucose and methyl-donor availability to Rag-dependent mTORC1 control and transcriptional adaptation.

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Declaration of competing interest The authors declare that they have no competing interests.

PubMed

NSUN2 links sugar and one-carbon metabolism to mTORC1 signaling controlled by Rag GTPases

Abstract

Full Text

Funding

Competing interests

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