The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.

Nuclear factor κB (NF-κB) signaling is a central pathway that participates in a variety of key processes, including immunity, inflammation, cell growth and differentiation. The activity of NF-κB is strictly regulated by a cluster of proteins, and modifications of these proteins either promote or suppress signal transduction at various steps. Here we demonstrated that HSCARG suppresses TNFα-stimulated NF-κB signaling under physiological conditions. We elucidated the detailed mechanism through which HSCARG inhibits NF-κB activation. HSCARG interacts with NEMO and suppresses polyubiquitination of NEMO by interacting with the deubiquitinase USP7. HSACRG attenuates its inhibitory effect on NEMO ubiquitination in USP7 knockdown cells, and inhibition of NEMO polyubiquitination by USP7 is impaired in HSCARG−/− cells as well. Moreover, we demonstrated that USP7 is a negative regulator of TNFα-stimulated NF-κB activity. Altogether, our data indicate that HSCARG and USP7 function in concert in inhibiting polyubiquination of NEMO, thus inhibiting NF-κB activity.

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