E3 Ligase Trim21 Ubiquitylates and Stabilizes Keratin 17 to Induce STAT3 Activation in Psoriasis

Keratin 17 (K17), a marker of keratinocyte hyperproliferation, is a type I intermediate filament that is overexpressed in psoriatic epidermis and plays a critical pathogenic role by stimulating T cells. However, the posttranslational modification of K17, which is reversible and targetable, has not been elucidated. Herein, we reported that K17 could be modified through ubiquitination that controlled its stability and led to the phosphorylation and nuclear translocation of its interactor signal transducers and activators of transcription 3 (STAT3), which is a key regulator of cell proliferation in psoriasis. First, we stimulated human keratinocyte cell line HaCaT cells with psoriasis (pso)-mix, which is a cytokine pool (IL-17, IL-22, tumor necrosis factor-α, and IFN-γ) mimicking the in vitro "psoriasis-like" status and found that the ubiquitination of K17 was essential to stabilize its protein expression in pso-mix-treated HaCaT cells. Subsequently, tripartite motif-containing protein 21 was identified as the E3 ligase of K17, which ubiquitylated K17 via K63 linkage to maintain K17 stabilization. More importantly, we uncovered that K17 was a direct interactor of STAT3, and K17 ubiquitination could promote STAT3 activation in pso-mix-treated HaCaT cells. Our study demonstrated that targeting K17 ubiquitination may be a potential therapeutic approach by attenuating STAT3 signaling in psoriasis.