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Published on: July 8, 2020
YTHDF2 Regulates Advanced Glycation End Products-Induced Melanogenesis through Inhibiting A20 Expression in Human
Jingjing Lan1, Xianyin Huang1, Hongpeng Li1
1Department of Dermato-Venereology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, P. R. China.
Abstract:
Fibroblast A20 suppresses advanced glycation end products (AGEs)-induced melanogenesis by inhibiting NLRP3 inflammasome activation. AGEs repress A20 expression and significantly m6A-methylate A20 mRNA in fibroblasts. YTHDF2 is the most studied m6A reader protein and can accelerate degradation of m6A-modified mRNA. Whether YTHDF2 regulates AGEs-induced A20 expression and pigmentation is unknown. In this study, we confirmed that YTHDF2 inversely regulated AGEs-BSA-inhibited A20 expression but facilitated AGEs-BSA-activated NF-κB signaling and NLRP3 inflammasome in fibroblasts via YTHDF2 knockdown and overexpression experiments. Mechanistically, YTHDF2 bound to m6A-modified A20 mRNA induced by AGEs-BSA and increased its degradation. Moreover, fibroblast YTHDF2 robustly promoted AGEs-BSA-induced IL-18 level in coculture supernatants and melanin content, tyrosinase activity, and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were significantly blocked by IL-18 binding protein. Further, fibroblast YTHDF2 markedly increased AGEs-BSA-induced epidermal melanin level in cocultured ex vivo skin and MAPKs activation in melanocytes. Importantly, upregulated dermal YTHDF2 expression was negatively correlated with dermal A20 level and positively associated with both epidermal melanin and dermal AGEs content in sun-exposed skin and lesions of melasma and solar lentigo. These findings suggest that fibroblast YTHDF2 positively regulates AGEs-induced melanogenesis mainly via A20/ NF-κB /NLRP3 inflammasome/ IL-18 /MAPKs axis in an m6A-dependent manner and functions in photoaging-induced hyperpigmentation skin disorders.
Insights
Fibroblast YTHDF2 promotes skin pigmentation by degrading A20 mRNA, activating inflammatory pathways like NLRP3 inflammasome, and exacerbating hyperpigmentation in conditions such as melasma.
Area of Science:
- Dermatology
- Molecular Biology
- Epigenetics
Background:
- Advanced glycation end products (AGEs) induce melanogenesis, a process influenced by fibroblast A20 expression.
- AGEs reduce A20 expression and modify its mRNA via m6A methylation, a process involving reader proteins like YTHDF2.
- The role of YTHDF2 in AGEs-induced melanogenesis and A20 regulation remained unclear.
Purpose of the Study:
- To investigate the role of YTHDF2 in regulating AGEs-induced melanogenesis in fibroblasts and melanocytes.
- To elucidate the molecular mechanisms by which YTHDF2 influences A20 expression and inflammatory signaling.
- To explore the association between YTHDF2 expression and hyperpigmentation in skin disorders.
Main Methods:
- Fibroblast and melanocyte cultures, YTHDF2 knockdown and overexpression, Western blotting, ELISA, melanin content assay, tyrosinase activity assay.
- Co-culture systems (fibroblasts and melanocytes), ex vivo skin models.
- Correlation analysis between YTHDF2, A20, AGEs, and melanin levels in human skin samples.
Main Results:
- YTHDF2 knockdown inhibited AGEs-induced NF-κB signaling, NLRP3 inflammasome activation, and IL-18 production.
- YTHDF2 directly bound to m6A-modified A20 mRNA, promoting its degradation and consequently enhancing melanogenesis.
- YTHDF2 overexpression in fibroblasts increased melanin content, tyrosinase activity, and MITF/tyrosinase expression in melanocytes, effects blocked by IL-18 binding protein.
- YTHDF2 upregulated epidermal melanin and MAPK activation in co-cultured skin models.
- Dermal YTHDF2 levels negatively correlated with A20 and positively with melanin and AGEs in sun-exposed skin and melasma/solar lentigo lesions.
Conclusions:
- Fibroblast YTHDF2 promotes AGEs-induced melanogenesis via an m6A-dependent pathway involving A20 degradation, NF-κB/NLRP3 inflammasome activation, and IL-18 signaling.
- YTHDF2 plays a significant role in photoaging-induced hyperpigmentation and related skin disorders like melasma and solar lentigo.
