Redox regulation of the m6A methyltransferase METTL3 in β cells controls the innate immune response in type 1 diabetes. Summary Type 1 diabetes ( T1D) is characterized by the destruction of pancreatic β cells. Several observations have renewed interest in β-cell RNA sensors and editors . Here, we report that N6-methyladenosine (m6A) is an adaptive β-cell protective mechanism that controls the amplitude and duration of the antiviral innate immune response at the onset of T1D. Levels of m6A methyltransferase 3 (METTL3 ) increase dramatically in β cells at the onset of type 1 diabetes, but decrease rapidly with disease progression. m6A sequencing revealed m6A hypermethylation of several key innate immune mediators including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-βH1 cells at the onset of type 1 diabetes. METTL3 silencing enhanced 2′ levels -5′-oligoadenylate synthetase by increasing the stability of its mRNA. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β cells delayed diabetes progression in the nonobese diabetic mouse model of type 1 diabetes . Mechanistically, accumulation of reactive oxygen species blocked the upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that cysteines at position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important for METTL3-mediated regulation of oligoadenylate synthase mRNA stability in cells. human β. Taken together, we report that m6A regulates the innate immune response at the β-cell level during the onset of T1D in humans. |
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Therapeutic targeting of the mechanistic pathway has the potential to slow disease progression in mice and humans
Around eight million people live with type 1 diabetes (T1D) worldwide, a chronic autoimmune disease in which the body attacks and destroys its own insulin-producing β cells in the pancreas, leading to a lack of insulin. and inability to regulate blood sugar. It is not known why the body suddenly perceives its own β cells as enemies; Some lines of evidence suggest that environmental factors such as viral infections can trigger the onset of type 1 diabetes, others suggest that genetics may also play some role.
Groundbreaking research by Joslin Diabetes Center researchers sheds new light on the specific changes that β cells undergo at the onset of Type 1 diabetes. Their findings, published in Nature Cell Biology , offer new avenues for targeted interventions for the chronic autoimmune disease. .
"In the field of type 1 diabetes, research has largely focused on understanding the immune component , but our study argues that the β cell plays an important role ," said Rohit N. Kulkarni, MD, Ph.D. , Margaret A. Congleton President and Co-Director of the Islet and Regenerative Biology Section at the Joslin Diabetes Center. “Our findings suggest that the β cell could be initiating key events that then promote the autoimmune mechanism to fail. “It is a paradigm-shifting approach.”
In a series of experiments using β cells taken from a mouse model of type 1 diabetes, as well as from humans with established type 1 diabetes, Kulkarni and colleagues unraveled the complex cascade of biochemical steps called the signaling pathway that controls the innate immune response. in the onset of type 1 diabetes. The team identified a pathway that influences the immune characteristics of β cells, acting as control switches that identify them as friends or enemies of the body. These control switches can be thought of as tiny labels. One specific tag the researchers focused on, called N6-methyladenosine (m6A), plays a vital role in the β-cell response during the onset of type 1 diabetes. By adjusting these control switches, the researchers were able to influence in the levels of a crucial protein along this pathway, leading to a notable delay in disease progression in a mouse model of type 1 diabetes.
Dario F. De Jesus MSc, Ph.D., senior author of the study and research associate in the Kulkarni laboratory, identified the key enzyme METTL3 as crucial for regulating β-cell antiviral defenses. In the later stages of type 1 diabetes, when METTL3 levels were low, this indicated that higher METTL3 levels protect β cells from dysfunction. By enhancing METTL3 production in the mouse model, the team successfully delayed disease progression.
"This discovery suggests that interventions to increase METTL3 levels are a potential strategy to protect β cells and slow the progression of type 1 diabetes," emphasized De Jesus, who is also an instructor in medicine at Harvard Medical School. .
Together, these various lines of evidence offer a clearer picture of the immunological events surrounding the still-mysterious emergence of type 1 diabetes, including a novel mechanism that could be exploited for β-cell protection. They also demonstrated that the METTL3 enzyme has the potential to promote β-cell survival and function during disease progression.
"It is notable that this pathway has commercially available compounds that have been used in the context of other diseases," said Kulkarni, who is also a professor of medicine at Harvard Medical School. “Although this is a different goal, it has been proven to be an approach that works. Among our next steps, we will focus on identifying specific molecules and pathways that can be leveraged to enhance β-cell protection.”
Co-authors included Natalie K. Brown, Ling Xiao, Jiang Hu, Garrett Fogarty, Sevim Kahraman and Giorgio Basile of the Joslin Diabetes Center; Zijie Zhang, Jiangbo Wei and Chuan He of the University of Chicago; Xiaolu Li, Wei-Jun Qian, and Matthew J. Gaffrey of the Pacific Northwest National Laboratory; Tariq M. Rana of the University of California, San Diego; Clayton Mathews and Mark A. Atkinson of the University of Florida College of Medicine; Alvin C. Powers of Vanderbilt University Medical Center; Audrey V. Mother of the University of California, San Francisco; Sirano Dhe-Paganon of Harvard Medical School; and Decio L. Eizirik of the Free University of Brussels.
This work is supported by the National Institutes of Health (grants R01 DK67536, UC4 DK116278, RM1 HG008935, and R01 DK122160). Portions of the mass spectrometry work were performed at the Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, a National Scientific User Facility sponsored by the Department of Energy under contract DE AC05-76RL0 1830. RNK gratefully acknowledges the support. by Margaret A. Congleton Endowed President and CH is an investigator at the Howard Hughes Medical Institute. DFDJ acknowledges support from the Mary K Iacocca Junior Postdoctoral Fellowship, American Diabetes Association (grant no. 7-21-PDF-140 and NIH K99 DK135927).
