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PreprintCited by 56Diabetes and associated disordersRNA modifications and cancerPancreatic function and diabetes

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Redox Regulation of m 6 A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes

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De Jesus, Dario F., Zhang, Zijie, Brown, Natalie K., Li, Xiaolu, Gaffrey, Matthew J., Kahraman, Sevim, Wei, Jiangbo, Hu, Jiang, Basile, Giorgio, Xiao, Ling, Rana, Tariq M., Mathews, Clayton, Powers, Alvin C., Atkinson, Mark A., Eizirik, Decio L., Dhe-Paganon, Sirano, Parent, Audrey V., Qian, Wei-Jun, He, Chuan, Kulkarni, Rohit N.·2023·Nature Cell Biology
DOI 10.1101/2023.02.16.528701PMC PMC11042681

Preprint — published as 10.1038/s41556-024-01368-0 · Paper page

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Abstract

SUMMARY: Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing β-cells. Several observations have renewed interest in the innate immune system as an initiator of the disease process against β-cells. Here, we show that N 6 -Methyladenosine (m 6 A) is an adaptive β-cell safeguard mechanism that accelerates mRNA decay of the 2’-5’-oligoadenylate synthetase (OAS) genes to control the antiviral innate immune response at T1D onset. m 6 A writer methyltransferase 3 (METTL3) levels increase drastically in human and mouse β-cells at T1D onset but rapidly decline with disease progression. Treatment of human islets and EndoC-βH1 cells with pro-inflammatory cytokines interleukin-1 β and interferon α mimicked the METTL3 upregulation seen at T1D onset. Furthermore, m 6 A-sequencing revealed the m 6 A hypermethylation of several key innate immune mediators including OAS1, OAS2, and OAS3 in human islets and EndoC-βH1 cells challenged with cytokines. METTL3 silencing in human pseudoislets or EndoC-βH1 cells enhanced OAS levels by increasing its mRNA stability upon cytokine challenge. Consistently, in vivo gene therapy, to prolong Mettl3 overexpression specifically in β-cells, delayed diabetes progression in the non-obese diabetic (NOD) mouse model of T1D by limiting the upregulation of Oas pointing to potential therapeutic relevance. Mechanistically, the accumulation of reactive oxygen species blocked METTL3 upregulation in response to cytokines, while physiological levels of nitric oxide promoted its expression in human islets. Furthermore, for the first time to our knowledge, we show that the cysteines in position C276 and C326 in the zinc finger domain of the METTL3 protein are sensitive to S-nitrosylation (SNO) and are significant for the METTL3 mediated regulation of OAS mRNA stability in human β-cells in response to cytokines. Collectively, we report that m 6 A regulates human and mouse β-cells to control the innate immune response during the onset of T1D and propose targeting METTL3 to prevent β-cell death in T1D.

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Metadata

Authors
De Jesus, D. F., Zhang, Z., Brown, N. K., Li, X., Gaffrey, M. J., Kahraman, S., Wei, J., Hu, J., Basile, G., Xiao, L., Rana, T. M., Mathews, C., Powers, A. C., Atkinson, M. A., Eizirik, D. L., Dhe-Paganon, S., Parent, A. V., Qian, W.-J., He, C., & Kulkarni, R. N.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Joslin Diabetes Center (US)
  • Pacific Northwest National Laboratory (US)
  • University of California San Diego (US)
  • University of Florida Health (US)
  • Vanderbilt University Medical Center (US)
  • Université Libre de Bruxelles (BE)
  • University of California, San Francisco (US)
Corresponding author
  • He, Chuan
  • Kulkarni, Rohit N.
ORCID
Venue
Nature Cell Biology
Publisher
openRxiv
Published
2023-02-16
Volume
26
Issue
3
Pages
421-437
ISSN
1465-7392 (ISSN-L)
DOI
10.1101/2023.02.16.528701
PMC
PMC11042681
OpenAlex
W4392157901
Cited by
56
References
1
Citations by year
2026: 17 · 2025: 20 · 2024: 18 · 2023: 1
FWCI
14.55
Type
journal article
Language
en
Open access
Locations
  • Nature Cell Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • U.S. Department of Energy (DE-AC05–76RL01830, DE-AC05?, DE-AC05-76RL0)
  • U.S. Department of Health and Human Services (RM1 HG008935, UC4 DK116278, K99 DK135927)
  • American Diabetes Association (7-21-PDF-140)
  • Brigham and Women's Hospital
  • Universitat Autònoma de Barcelona
  • National Institutes of Health (P30 DK36836, DK 36836, DE-AC05-76RL01830)
  • Advanced Research Projects Agency - Energy (DE-AC05-76RL01830)
  • ULB Center for Diabetes Research
  • National Human Genome Research Institute (RM1HG008935)
  • National Institute of Allergy and Infectious Diseases (P01AI042288)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK122160, K99DK135927, UC4DK116278, P30DK036836, R01DK067536, R00DK135927)
  • Pacific Northwest National Laboratory (DEAC0576RL01830)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Keywords
type 1 diabetes, pancreatic beta cells, METTL3, N6-methyladenosine, RNA methylation, innate immune response, antiviral response, 2',5'-oligoadenylate synthetase, ADAR1, mRNA stability, reactive oxygen species, nitric oxide, S-nitrosylation, zinc finger, gene therapy, NOD mice, islets

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