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NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Authors :
Chen T
Xu ZG
Luo J
Manne RK
Wang Z
Hsu CC
Pan BS
Cai Z
Tsai PJ
Tsai YS
Chen ZZ
Li HY
Lin HK
Source :
Cell metabolism [Cell Metab] 2023 Oct 03; Vol. 35 (10), pp. 1782-1798.e8. Date of Electronic Publication: 2023 Aug 15.
Publication Year :
2023

Abstract

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 m <superscript>5</superscript> C 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 <superscript>+</superscript> 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.<br />Competing Interests: Declaration of interests H.-K.L. is a consultant for Stablix, Inc.<br /> (Copyright © 2023 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1932-7420
Volume :
35
Issue :
10
Database :
MEDLINE
Journal :
Cell metabolism
Publication Type :
Academic Journal
Accession number :
37586363
Full Text :
https://doi.org/10.1016/j.cmet.2023.07.009