Dr. Lee, Yungling Leo李永凌 博士

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FUT8 remodeling of EGFR regulates epidermal keratinocyte proliferation during psoriasis development

Journal of Investigative Dermatology, Sep 02, 2020

Abstract

α-(1,6)-fucosyltransferase (FUT8) is implicated in the pathogenesis of several malignancies, but its role in psoriasis is poorly understood. Here, we show that FUT8 remodeling of epidermal growth factor receptor (EGFR) plays a critical role in the development of psoriasis phenotypes. Notably, elevated FUT8 expression was associated with disease severity in the lesional epidermis of a psoriasis patient. FUT8 gain-of-function promoted HaCaT cell proliferation while shFUT8 reduced cell proliferation and induced a longer S-phase, with downregulation of cyclin A1 expression. Furthermore, cell proliferation, which is controlled by activation of EGFR was shown to be regulated by FUT8 core-fucosylation of EGFR. shFUT8 significantly reduced EGFR/AKT signaling and slowed EGF-EGFR complex trafficking to the perinuclear region. Moreover, shFUT8 reduced ligand induced EGFR dimerization. Over-activated EGFR was observed in the lesional epidermis of both human patient and psoriasis-like mouse model. Whereas, conditional-knockout of FUT8 in an IL23 psoriasis-like mouse model ameliorated disease phenotypes and reduced EGFR activation in the epidermis. These findings implied that elevated FUT8 expression in the lesional epidermis is implicated in the development of psoriasis phenotypes, being required for EGFR over-activation and leading to keratinocyte hyper-proliferation.

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