METTL14 promotes IL‐6‐induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27

• Published in: Journal of cellular and molecular medicine Vol. 28; no. 3; pp. e18085 - n/a
• Main Authors: Chen, Yiran, Xiang, Yanwei, Miao, Xiao, Kuai, Le, Ding, Xiaojie, Ma, Tian, Li, Bin, Fan, Bin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2024; John Wiley and Sons Inc
• Subjects: Acidification; Adenine - analogs & derivatives; Animals; Cell viability; Cholecystokinin; Cytokines; DNA-Binding Proteins; Glucose; Glycolysis; HaCaT Cells; Humans; IL‐6; Imiquimod; Immunohistochemistry; Inflammation; Inflammation - pathology; Inflammatory diseases; Interleukin 6; Interleukin-6 - pharmacology; Keratinocytes; Keratinocytes - pathology; Laboratory animals; m6A methylation; Methyltransferases; METTL14; Mice; mRNA; N6-methyladenosine; Nuclear Proteins; Original; Oxygen consumption; Proteins; Psoriasis; Psoriasis - pathology; Reagents; RNA-Binding Proteins; Signal transduction; Skin diseases; Skin lesions; Stat3 protein; Transcription Factors; TRIM27; Tripartite Motif Proteins; United States > US; China; m6A methylation; METTL14; TRIM27; psoriasis; IL-6
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.18085

Interleukin‐6 (IL‐6) is a cytokine generated by healthy constituents of the skin, but is also up‐regulated by a wide range of skin lesions and inflammatory conditions to trigger cytopathy of skin cells. TRIM27 was identified to contribute to the functional effects of IL‐6 on skin cells. However, the underlying mechanism was not clear. Lentivirus infection was used for gene overexpression or silencing. RT‐PCR and Western blot were used to respectively assess mRNA and protein levels. Cell viability was assessed by CCK‐8 assay. Extracellular flux analysis was used to assess the levels of oxygen consumption rate and extracellular acidification rate. Mouse back skin was treated with imiquimod to produce psoriasis‐like inflammation in vivo. Histological assessment and immunohistochemistry staining were respectively applied to analyse lesioned mouse and human skin samples. IL‐6‐induced increased viability, glycolysis and inflammation in keratinocytes was inhibited both by a chemical methylation inhibitor and by METTL14 knockdown. Further investigation found that METTL14 induces m6A methylation of TRIM27, which is recognized by a m6A reader, IGF2BP2. Elevation of TRIM27 level and activation of IL‐6/STAT3 signalling pathway were found in an in vivo psoriasis‐like inflammation model, whereas inhibition m6A methylation strongly alleviated the inflammation. Finally, METTL14, TRIM27, STAT3, p‐STAT3 and IL‐6 expressions were all found to be increased in clinical skin samples of psoriatic patients. Our results unravelled METTL14/TRIM27/IGF2BP2 signalling axis in keratinocyte cytopathy, which plays a critical role in facilitating the activation of IL‐6/STAT3 signalling pathway. Our findings should provide inspirations for the design of new therapeutics for skin inflammatory diseases including psoriasis.