NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.
Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.
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Related Subject Headings
- Signal Transduction
- Nucleotidyltransferases
- Methyltransferases
- Immunotherapy
- Humans
- Endocrinology & Metabolism
- Carcinogenesis
- 3205 Medical biochemistry and metabolomics
- 3101 Biochemistry and cell biology
- 1101 Medical Biochemistry and Metabolomics
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Signal Transduction
- Nucleotidyltransferases
- Methyltransferases
- Immunotherapy
- Humans
- Endocrinology & Metabolism
- Carcinogenesis
- 3205 Medical biochemistry and metabolomics
- 3101 Biochemistry and cell biology
- 1101 Medical Biochemistry and Metabolomics