USP16 drives psoriasis progression by deubiquitinating and stabilizing NLRP3 in keratinocytes
Nan Wang, Fangqian Guan, Yifan Lin, Bohao Sun, Jindan Dai, Xiejun Xu, Weibo Tang, Yanhua Ren, Xuliang Huang, Wenjie Gao, Xixi Chen, Litai Jin, Weitao Cong, Zhongxin Zhu
Nan Wang, Fangqian Guan, Yifan Lin, Bohao Sun, Jindan Dai, Xiejun Xu, Weibo Tang, Yanhua Ren, Xuliang Huang, Wenjie Gao, Xixi Chen, Litai Jin, Weitao Cong, Zhongxin Zhu
View: Text | PDF
Research Article Cell biology Dermatology

USP16 drives psoriasis progression by deubiquitinating and stabilizing NLRP3 in keratinocytes

Abstract

Psoriasis is a chronic inflammatory dermatosis characterized by pathological keratinocyte hyperproliferation and dysregulated immune activation. While ubiquitin-specific peptidase 16 (USP16) has been implicated in modulating multiple cellular signaling pathways, its functional role in psoriatic pathogenesis remains poorly understood. Our investigation revealed pronounced upregulation of USP16 expression in psoriatic epidermis compared with normal controls. Keratinocyte-specific USP16 knockdown demonstrated remarkable therapeutic efficacy, significantly ameliorating characteristic psoriatic phenotypes including epidermal hyperplasia and inflammatory infiltration. RNA-seq analysis showed that USP16 has substantial effects on cell cycle transition and keratinocytes proliferation. Through KEGG analysis, it was found that USP16 primarily regulates the NLRP3 signaling pathway, leading to enhanced cell proliferation and inflammation. Mechanically, USP16 directly binds to the NLRP3 protein to eliminate K48 ubiquitination modification, enhancing the stability of the NLRP3 protein, activating inflammasome activity. Further studies showed that the therapeutic effects of reducing USP16 on psoriasis progression were counteracted by an NLRP3 activator and keratinocyte-specific NLRP3 overexpression adenovirus. Collectively, these results shed light on how USP16 promotes NLRP3 signaling in keratinocytes, exacerbating psoriasis development. This positive regulation highlights the potential of USP16 as a therapeutic target for psoriasis.

Authors

Nan Wang, Fangqian Guan, Yifan Lin, Bohao Sun, Jindan Dai, Xiejun Xu, Weibo Tang, Yanhua Ren, Xuliang Huang, Wenjie Gao, Xixi Chen, Litai Jin, Weitao Cong, Zhongxin Zhu

×

Figure 7

Keratinocyte-specific knockdown of USP16 alleviates IL-23–induced psoriasis phenotype.

Options: View larger image (or click on image) Download as PowerPoint
Keratinocyte-specific knockdown of USP16 alleviates IL-23–induced psoria...
(A) Schematic diagram demonstrating the animal experiment design. (B) Immunoblotting and quantitative analysis of USP16 protein levels in PBS and IL-23–treated mice. β-Actin was used as a loading control (n = 5). (C) Representative IHC staining for USP16 expression in PBS and IL-23–induced psoriasis lesions (n = 5). Scale bars: 100 μm. (D) Immunoblotting and quantitative analysis of Cyclin A1, Cyclin E1, and Bcl-2 protein levels in the skin from AAV-GFP and AAV-Cre mice were treated with IL-23. β-Actin was used as a loading control (n = 5). (E) Representative histological sections of the dorsal back from AAV-GFP and AAV-Cre mice were treated with IL-23 and stained with H&E, and quantification of the epidermal thickness was analyzed (n = 5). Scale bars: 200 μm. (F) Representative IHC staining for Ki-67 expression in the skin from AAV-GFP and AAV-Cre mice treated with IL-23 (n = 5). Scale bar: 100 μm. Data are shown as the mean ± SEM. **P < 0.01, ***P < 0.001. The P value was determined using unpaired, 2-tailed Student’s t test (B–F). All numbers (n) are biologically independent experiments.