Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis

Zhikai Wang, Yang Sun, Fangzhou Lou, Jing Bai, Hong Zhou, Xiaojie Cai, Libo Sun, Qianqian Yin, Sibei Tang, Yue Wu, Li Fan, Zhenyao Xu, Hong Wang, Xiaoyu Hu and Honglin Wang ()
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Zhikai Wang: Shanghai Jiao Tong University School of Medicine
Yang Sun: Shanghai Jiao Tong University School of Medicine
Fangzhou Lou: Shanghai Jiao Tong University School of Medicine
Jing Bai: Shanghai Jiao Tong University School of Medicine
Hong Zhou: Shanghai Jiao Tong University School of Medicine
Xiaojie Cai: Shanghai Jiao Tong University School of Medicine
Libo Sun: Shanghai Jiao Tong University School of Medicine
Qianqian Yin: Shanghai Jiao Tong University School of Medicine
Sibei Tang: Shanghai Jiao Tong University School of Medicine
Yue Wu: Shanghai Jiao Tong University School of Medicine
Li Fan: Shanghai Jiao Tong University School of Medicine
Zhenyao Xu: Shanghai Jiao Tong University School of Medicine
Hong Wang: Shanghai Jiao Tong University School of Medicine
Xiaoyu Hu: Tsinghua University
Honglin Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Protein Phosphatase 6 down-regulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis, indicating that restoration of protein phosphatase 6 can be a rational strategy for psoriasis treatment. Through the phenotypic screen, we here identify L-menthol that ameliorates psoriasis-like skin inflammation by increasing protein phosphatase 6 in keratinocytes. Target identification approaches reveal an indispensable role for the transcription factor hairy and enhancer of split 1 in governing the protein phosphatase 6-upregulating function of L-menthol in keratinocytes. The transcription factor hairy and enhancer of split 1 is diminished in the epidermis of psoriasis patients and imiquimod-induced mouse model, while L-menthol upregulates the transcription factor hairy and enhancer of split 1 by preventing its proteasomal degradation. Mechanistically, the transcription factor hairy and enhancer of split 1 transcriptionally activates the expression of immunoglobulin-binding protein 1 which promotes protein phosphatase 6 expression and inhibits its ubiquitination. Collectively, we discover a therapeutic compound, L-menthol, for psoriasis, and uncover the dysfunctional the transcription factor hairy and enhancer of split 1- immunoglobulin-binding protein 1- protein phosphatase 6 axis that contributes to psoriasis pathology by using L-menthol as a probe.

Date: 2022
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DOI: 10.1038/s41467-022-35565-y

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