STUB1 Regulates Epithelial Function Through Mediating the EDAR/ NF-κB Pathway

Besides ectodermal derivatives morphogenesis, the inactivation of the Ectodysplasin A(EDA)/Ectodysplasin A Receptor(EDAR) signaling pathway has also been demonstrated to impede the process of skin repair. EDAR, a member of the tumor necrosis factor receptor superfamily, plays a central role in this signaling pathway.However, the regulatory mechanism of EDAR and its target genes in wound healing remain unclear.As a membrane protein, the turnover of EDAR is more likely to be affected by ubiquitination, where an E3 Ubuitin ligase targets substrates for degradation. We performed a yeast two-hybrid assay to identify the potential E3 ligase. STIP1 homology and U-box-containing protein 1 (STUB1) was found to interact with EDAR and mediate its ubiquitination and degradation. To explore the function of STUB1 in keratinocytes, we constructed STUB1 knockout HaCaT cells, which showed accelerated healing and growth capabilities. Elevated protein level of EDAR and upregulated activation of downstream nuclear factor-κB signaling were detected in STUB1 knockout HaCaT cells. To find out why STUB1 knockout induced the functional alteration of HaCaT cells and which genes might be affected, an RNA-seq analysis was performed.