METTL16 improves cigarette smoking-induced COPD emphysema through inhibiting autophagy by mediating pri-miR-511 m6A modification.

Abstract

Cigarette smoke is a significant cause of COPD emphysema through several underlying mechanisms. METTL16, a prominent methyltransferase, mediates N6-methyladenosine (m6A) modification in mRNA, lncRNA and snRNA, while METTL16-mediated m6A modification of pri-miRNA in CS-COPD emphysema remains unexplored. RT-qPCR and immunochemistry techniques showed obviously downregulated METTL16 in lung samples from patients with COPD. An alveolar epithelium-specific METTL16 knockout mouse model was constructed, which exhibited more severe pathological changes characteristic of CS-COPD in the lungs. METTL16 overexpression prevented the accumulation of autophagy induced by cigarette smoke extract (CSE), but METTL16 silencing had the reverse effect. In this study, we detected reduced m6A-modified pri-miR-511 and increased nuclear receptor 4A1 (NR4A1) transcript using methylated RNA immunoprecipitation (MeRIP) and mRNA microassay, respectively in lung tissues from patients with COPD. Mechanistically, METTL16 upregulation enhanced the expression of miR-511-3p via m6A modification, which inhibited CSE-mediated autophagy. Bioinformatics analysis and dual luciferase reporter gene detection system confirmed the interplay between miR-511-3p and NR4A1. Transfection of miR-511-3p mimic reduced NR4A1 expression, thereby reducing autophagy in vitro. Additionally, METTL16 alleviated CSE-induced autophagy via controlling NR4A1 expression. Therefore, we determined that METTL16 could play a beneficial role in CS-induced COPD emphysema through relieving autophagy by the miR-511-3p/NR4A1 axis in an m6A-dependent manner.