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

Author:

Wang Zhikai,Sun Yang,Lou Fangzhou,Bai Jing,Zhou Hong,Cai Xiaojie,Sun LiboORCID,Yin Qianqian,Tang Sibei,Wu Yue,Fan Li,Xu Zhenyao,Wang Hong,Hu XiaoyuORCID,Wang HonglinORCID

Abstract

AbstractProtein 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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