Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China.
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
J Invest Dermatol. 2018 Dec;138(12):2568-2577. doi: 10.1016/j.jid.2018.05.016. Epub 2018 May 31.
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.
角蛋白 17（K17）是一种角蛋白细胞过度增殖的标志物，是一种 I 型中间丝，在银屑病表皮中过度表达，并通过刺激 T 细胞发挥关键的致病作用。然而，K17 的翻译后修饰（即可逆且可靶向的修饰）尚未阐明。在此，我们报道 K17 可以通过泛素化修饰进行修饰，这种修饰可以控制其稳定性，并导致其相互作用的信号转导和转录激活因子 3（STAT3）的磷酸化和核转位，而 STAT3 是银屑病中细胞增殖的关键调节因子。首先，我们用银屑病混合细胞因子（pso-mix，包含 IL-17、IL-22、肿瘤坏死因子-α和 IFN-γ）刺激人角质形成细胞系 HaCaT 细胞，模拟体外“银屑病样”状态，发现 K17 的泛素化对于稳定 pso-mix 处理的 HaCaT 细胞中的 K17 蛋白表达至关重要。随后，鉴定出三结构域蛋白 21 是 K17 的 E3 连接酶，通过 K63 连接泛素化 K17，以维持 K17 的稳定性。更重要的是，我们发现 K17 是 STAT3 的直接相互作用蛋白，K17 的泛素化可以促进 pso-mix 处理的 HaCaT 细胞中 STAT3 的激活。我们的研究表明，通过抑制银屑病中的 STAT3 信号通路，靶向 K17 泛素化可能是一种潜在的治疗方法。
