Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis

Junqin Li; Ying Wang; Xuping Niu; Jianxiao Xing; Yu Dou; Yuanjun Yao; Yanyang Liang; Zehong Wang; Qiang Wang; Haiyan Feng; Aihong Peng; Yi Guo; Huifang Liang; Yaxin Guo; Juan Li; Ruixia Hou; Yueai Cheng; Tong Qu; Xinhua Li; Guohua Yin; Kaiming Zhang

doi:10.1093/bjd/ljae194

Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis

Br J Dermatol. 2024 May 16:ljae194. doi: 10.1093/bjd/ljae194. Online ahead of print.

Authors

Junqin Li¹, Ying Wang¹, Xuping Niu¹, Jianxiao Xing¹, Yu Dou¹, Yuanjun Yao¹, Yanyang Liang¹, Zehong Wang¹, Qiang Wang¹, Haiyan Feng¹, Aihong Peng¹, Yi Guo¹, Huifang Liang¹, Yaxin Guo¹, Juan Li¹, Ruixia Hou¹, Yueai Cheng¹, Tong Qu¹, Xinhua Li¹, Guohua Yin¹, Kaiming Zhang¹

Affiliation

¹ Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Central Hospital, Taiyuan 030009, China.

PMID: 38752336
DOI: 10.1093/bjd/ljae194

Abstract

Background: Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases.

Objective: To investigate the abnormal Khib profile and its pathogenic role in psoriasis.

Methods: We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis.

Results: The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression.

Conclusion: Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.