1. AS3MT facilitates NLRP3 inflammasome activation by m 6 A modification during arsenic-induced hepatic insulin resistance.
- Author
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Qiu T, Wu C, Yao X, Han Q, Wang N, Yuan W, Zhang J, Shi Y, Jiang L, Liu X, Yang G, and Sun X
- Subjects
- Humans, Diabetes Mellitus, Type 2 metabolism, Inflammasomes metabolism, Liver, Methyltransferases genetics, Methyltransferases metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Proteins metabolism, Arsenic toxicity, Arsenic metabolism, Insulin Resistance
- Abstract
N6-methyladenosine (m
6 A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6 A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)- Published
- 2023
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