Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes

De Jesus, Dario F.; Zhang, Zijie; Brown, Natalie K.; Li, Xiaolu; Xiao, Ling; Hu, Jiang; Gaffrey, Matthew J.; Fogarty, Garrett; Kahraman, Sevim; Wei, Jiangbo; Basile, Giorgio; Rana, Tariq M.; Mathews, Clayton; Powers, Alvin C.; Parent, Audrey V.; Atkinson, Mark A.; Dhe-Paganon, Sirano; Eizirik, Decio L.; Qian, Wei-Jun; He, Chuan; Kulkarni, Rohit N.

doi:10.1038/s41556-024-01368-0

Title: Redox regulation of m⁶A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes

Journal Article · 25 February 2024 · Nature Cell Biology

DOI: https://doi.org/10.1038/s41556-024-01368-0 · OSTI ID:2407043

^[1]; Zhang, Zijie ^[2]; Brown, Natalie K. ^[1];

^[3]; Xiao, Ling ^[1]; Hu, Jiang ^[1]; Gaffrey, Matthew J. ^[3]; Fogarty, Garrett ^[1]; Kahraman, Sevim ^[1];

^[4]; Basile, Giorgio ^[1]; Rana, Tariq M. ^[5]; Mathews, Clayton ^[6]; Powers, Alvin C. ^[7]; Parent, Audrey V. ^[8]; Atkinson, Mark A. ^[6]; Dhe-Paganon, Sirano ^[1];

^[9];

^[3];

^[2] more »

Harvard Medical School, Boston, MA (United States)
Univ. of Chicago, IL (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
National Univ. of Singapore (Singapore); Univ. of Chicago, IL (United States)
Univ. of California San Diego, La Jolla, CA (United States)
Univ. of Florida, Gainesville, FL (United States)
Vanderbilt Univ., Nashville, TN (United States)
Univ. of California, San Francisco, CA (United States)
Univ. Libre de Bruxelles, Brussels (Belgium)

Type 1 Diabetes (T1D) is characterized by the destruction of pancreatic ß-cells. Several observations have renewed the interest in ß-cell RNA sensors and editors. Here, in this study, we report that N⁶-methyladenosine (m⁶A) is an adaptive ß-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m⁶A writer methyltransferase 3 (METTL3) levels increase drastically in ß-cells at T1D onset but rapidly decline with disease progression. m⁶A-sequencing revealed the m⁶A hypermethylation of several key innate immune mediators including OAS1, OAS2, OAS3, and ADAR1 in human islets and EndoC-ßH1 cells at T1D onset. METTL3 silencing enhanced OAS levels by increasing its mRNA stability. Consistently, in vivo gene therapy, to prolong Mettl3 overexpression specifically in ß-cells, delayed diabetes progression in the non-obese diabetic (NOD) mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced its expression. Furthermore, for the first time to our knowledge, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation (SNO) and are significant for the METTL3-mediated regulation of OAS mRNA stability in human ß-cells. Collectively, we report that m⁶A regulates ß-cells to control the innate immune response during the onset of T1D in humans.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH); American Diabetes Association (ADA)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2407043

Report Number(s):: PNNL-SA--192085

Journal Information:: Nature Cell Biology, Journal Name: Nature Cell Biology Journal Issue: 3 Vol. 26; ISSN 1465-7392

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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Additional file 1 of METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA Wang, Qiuyun; Shen, Jie; Luo, Shiyuan figshare https://doi.org/10.6084/m9.figshare.26308937.v1	image	January 2024

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59 BASIC BIOLOGICAL SCIENCES
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METTL3
Type 1 diabetes
antiviral innate immunity
m6A
mRNA methylation
s-nitrosylation
ß-cells

Title: Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes

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Title: Redox regulation of m⁶A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes