FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

Author:

Gao Yue1,Zhou Wei1,Zhang Pengfei,Yang Ju2,Liu Xiong3,Huang Congshu1,Tao Yuandong4,Shen Pan1,Xiao Chengrong1,Zhou Lei1,Li Gaofu1,Zhang Li3

Affiliation:

1. Beijing Institute of Radiation Medicine

2. The General Hospital of Western Theater Command PLA

3. The PLA Center for Disease Control and Prevention

4. The Seventh Medical Center of Chinese PLA General Hospital

Abstract

Abstract Keratinocyte proliferation and differentiation in epidermis are well controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose 1, 6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. FBP1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. FBP1 deficiency in mice facilitates psoriasis development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

Publisher

Research Square Platform LLC

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