Downregulation of lysine 2-hydroxyisobutyrylation of ErbB3 binding protein 1 at amino acid 210 promotes keratinocyte proliferation via induction of transcription initiation factor IA-mediated rRNA synthesis

BACKGROUND: Psoriasis is a prevalent chronic inflammatory dermatosis characterized by the excessive proliferation of keratinocytes (KCs). Lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been associated with the development of autoimmune diseases. OBJECTIVES: To investigate the abnormal Khib modification profile and its pathogenic role in psoriasis. METHODS: Liquid chromatography-tandem mass spectrometry was used to analyse Khib-modified proteins in the epidermis of psoriasis lesions and healthy control skin. Mutated cells and mice with downregulated Khib modification of ErbB3 binding protein 1 (EBP1) at amino acid 210 (EBP1Khib210) were generated, to investigate the functional effects of EBP1Khib210 in psoriasis. RESULTS: Omics analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared with controls. We found downregulation of EBP1Khib210 in psoriatic lesions and mice with imiquimod-induced psoriasis. Notably, expression of EBP1Khib210 was upregulated in patients with psoriasis following effective treatment. Decreased EBP1Khib210 enhanced KC viability, proliferation and survival but inhibited apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced KC proliferation. Moreover, we found that the EBP1K210A mutation increased the interaction between EBP1 and nuclear protein kinase B (Akt), thereby inhibiting mouse double minute 2-mediated transcription initiation factor IA (TIF-IA) ubiquitination and resulting in increased rRNA synthesis and KC proliferation. Downregulation of EBP1Khib210 was attributed to an inflammation-induced increase in histone deacetylase 2 expression. CONCLUSIONS: Downregulation of EBP1Khib210 promoted KC proliferation by modulating Akt signalling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.