METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome

Abstract

N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m6A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of m6A RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of m6A RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS in vivo and in vitro. Furthermore, we identified tripartite motif-containing (Trim)59 as a key m6A effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS via m6A modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury.

An overview of the effects and mechanisms of m6 A methylation on innate immune cells in sepsis

“…Chen et al. ( 39 ) have found that in sepsis, the reduction of m 6 A modification is associated with the down-regulation of METTL3. METTL3 knockout can accelerate barrier dysfunction and inflammatory response.…”

“…Abnormal m 6 A methylation is responsible for the occurrence and development of human diseases, suggesting the vital role of m 6 A modification in different genomic backgrounds. Chen et al (39) have found that in sepsis, the reduction of m 6 A modification is associated with the downregulation of METTL3. METTL3 knockout can accelerate barrier dysfunction and inflammatory response.…”

Personalized medicine using omics approaches in acute respiratory distress syndrome to identify biological phenotypes

“…Comparing mRNA in 300 patients with ARDS and 300 controls, TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 SNPs were identified as markers of increased risk for ARDS and a poor prognosis [ 142 ]. N-Methyl-adenosine modification of Trim59 RNA was protective against the risk of developing ARDS during sepsis [ 143 ]. The mRNA levels of p300, CREB binding protein, tyrosine-protein kinase transmembrane receptor γt, and plasma concentration of IL-17, IL-6 were higher in patients with acute ARDS compared with controls, whereas p300/CBP expression was a risk factor for 28-day mortality [ 144 ].…”

Interaction between N6-methyladenosine and autophagy in the regulation of bone and tissue degeneration

“…m6A modification is one of the most abundant modifications in eukaryotic mRNA and is regulated by both m6A methyltransferase and demethylase, which are specifically recognized and bound by the m6A recognition protein ( Chen et al, 2022a ). m6A modification is dynamically controlled by “writers”, “erasers”, and the “readers”, which are the main methylation-related reading proteins ( Table 1 ) ( Shen et al, 2022a ).…”