IL‐17C‐Mediated Upregulation of SMURF2 Induces Psoriatic Changes in Keratinocytes by Facilitating PPP6C Ubiquitination

ABSTRACT Psoriasis, a persistent inflammatory skin condition, affects approximately 2%–3% of the world's population. Increased IL‐17C levels are noted in psoriatic lesions, alongside IL‐17's ability to diminish protein phosphatase 6 catalytic subunit (PPP6C) expression in keratinocytes. Additionally, SMAD‐specific E3 ubiquitin protein ligase 2 (SMURF2) facilitates the degradation of specific substrates through ubiquitination. However, the precise mechanisms of action involving IL‐17C, SMURF2, and PPP6C in psoriasis remain unclear. Therefore, this study aims to delve into how IL‐17C, SMURF2, and PPP6C contribute to psoriasis development. A psoriasis mice model was established using 5% imiquimod cream. And the expression of IL‐17C, SMURF2, and PPP6C was tested. Further, an investigation was conducted using experimental techniques such as CCK‐8, flow cytometry, colony formation assay, ELISA, qRT‐PCR, western blot assay, co‐immunoprecipitation, and ubiquitination assays. Employing both lentiviral transfection and plasmid transfection methods, an in‐depth investigation was conducted into the contributions of IL‐17C, SMURF2, and PPP6C to psoriasis. The results showed that the IL‐17C, Keratin 17 and SMURF2 were increased, and PPP6C was decreased in psoriasis mice model. Further, IL‐17C enhanced the cell viability of human epidermal keratinocytes (HaCaT), induced inflammatory responses, and upregulated SMURF2 and Keratin 17 expression. When SMURF2 was silenced, the effects of IL‐17C on HaCaT cells were significantly inhibited. Moreover, SMURF2 interacted with PPP6C, promoting its ubiquitination and degradation. Overexpression of SMURF2 further enhanced the effects of IL‐17C on HaCaT cells by targeting PPP6C. In conclusion, our study uncovered the upregulation of SMURF2 mediated by IL‐17C, leading to psoriasis‐like alterations in keratinocytes through the promotion of PPP6C ubiquitination. This novel finding not only provides crucial insights into the molecular mechanisms of psoriasis but also offers potential avenues for innovative therapeutic strategies targeting this mechanism.