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FTO promotes innate immunity by controlling NOD1 expression via m⁶A-YTHDF2 manner in teleost.

ABSTRACT: N6-methyladenosine (m⁶A), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating innate immunity. However, its underlying mechanism remains largely unknown, especially in lower vertebrates. The results of the present study show that fat-mass- and obesity-associated protein (FTO), also known as a m⁶A demethylase, improved the innate immunity and prevented Siniperca chuatsi rhabdo virus and Vibrio anguillarum infection in miiuy croaker. Significantly, FTO-promoted immunity was dependent on its m⁶A demethylase activity. In terms of mechanism, NOD1 has abundant methylation modification in its CDS and 3'UTR regions, and FTO can reduce its methylation level, thus avoiding its degradation by YTHDF2. In summary, our results indicate that the FTO-mediated m⁶A modification in NOD1 mRNA promotes innate immunity by activating the NOD-like receptor pathway, which provides a molecular mechanism for the regulation of immune response via RNA methylation in teleost.

SUBMITTER: Geng S

PROVIDER: S-EPMC9722488 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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FTO promotes innate immunity by controlling NOD1 expression via m6A-YTHDF2 manner in teleost.

Geng Shang S Zheng Weiwei W Zhao Yan Y Xu Tianjun T

iScience 20221122 12

N6-methyladenosine (m6A), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating innate immunity. However, its underlying mechanism remains largely unknown, especially in lower vertebrates. The results of the present study show that fat-mass- and obesity-associated protein (FTO), also known as a m6A demethylase, improved the innate immunity and prevented Siniperca chuatsi rhabdo virus and Vibrio anguillarum infection in mi ...[more]

PMID: 36483010

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Project description:BackgroundAdolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated.MethodsWe investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its m6A reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression.ResultsFTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises.ConclusionsFTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.

Project description:ObjectiveInsulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance.Research design and methodsMetabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2(-/-) double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid-containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro.ResultsNOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1(-/-), mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice.ConclusionsWe identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism.

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FTO promotes innate immunity by controlling NOD1 expression via m⁶A-YTHDF2 manner in teleost.

Publications

FTO promotes innate immunity by controlling NOD1 expression via m<sup>6</sup>A-YTHDF2 manner in teleost.

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