FUT8 Remodeling of EGFR Regulates Epidermal Keratinocyte Proliferation during Psoriasis Development

Abstract

α-(1,6)-fucosyltransferase 8 (FUT8) is implicated in the pathogenesis of several malignancies, but its role in psoriasis is poorly understood. In this study, we show that FUT8 remodeling of 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 patient with psoriasis. FUT8 gain of function promoted HaCaT cell proliferation, whereas short hairpin FUT8 reduced cell proliferation and induced a longer S phase with downregulation of cyclin A1 expression. Furthermore, cell proliferation, which is controlled by the activation of EGFR, was shown to be regulated by FUT8 core fucosylation of EGFR. Short hairpin FUT8 significantly reduced EGFR/protein kinase B signaling and slowed EGF‒EGFR complex trafficking to the perinuclear region. Moreover, short hairpin FUT8 reduced ligand-induced EGFR dimerization. Overactivated EGFR was observed in the lesional epidermis of both human patient and psoriasis-like mouse model, whereas conditional knockout of FUT8 in an IL-23 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 overactivation and leading to keratinocyte hyperproliferation.