2. Academic Validation
  3. Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells

Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells

  • Clin Immunol. 2023 Dec 24:259:109883. doi: 10.1016/j.clim.2023.109883.
Fang Wang 1,  Xin Gu 2,  Shiyu Lin 3,  Qin Wu 3,  Yuankai Sun 3,  Qian Zhang 3,  Aishu Luo 3,  Xiaoke Feng 4,  Lei Wang 3,  Lingxiao Xu 3,  Wei Sun 5,  Wenfeng Tan 6
Affiliations

Affiliations

  • 1 Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 2 Department of Cardiology, the Affiliated Hospital of Jiangnan University, Wuxi 214125, China.
  • 3 Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 4 Department of Traditional Chinese Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Integrated Traditional Chinese and Western Medicine Institute of Nanjing Medical University, Nanjing 210029, China.
  • 5 Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: weisun7919@njmu.edu.cn.
  • 6 Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: tw2006@njmu.edu.cn.
PMID: 38147957 DOI: 10.1016/j.clim.2023.109883
Abstract

Abnormalities of regulatory T cells (Tregs) has been suggested in rheumatoid arthritis (RA), and Forkhead box P3 (Foxp3) is the key transcriptional factor of Tregs expression. However, the underlying molecular mechanism remains unclear. Here, we demonstrated peptidase inhibitor 16 (PI16) was significantly increased in the peripheral blood, synovial fluid, and synovial tissue from RA patients. PI16 transgenic mice (PI16Tg) aggravated arthritis severity partly through suppressing Foxp3 expression. Mechanistically, PI16 could interact with and stabilize Bmi-1 in Tregs via inhibiting K48-linked polyubiquitin of Bmi-1, which promotes the enrichment of repressive histone mark in Foxp3 promoter. Furthermore, Bmi-1 specific inhibitor PTC209 could restore Foxp3 expression and alleviate arthritis progression in PI16Tg mice, accompanied by increased recruitment of active histone mark in the promoter of Tregs. Our results suggest that PI16-Bmi-1 axis plays an important role in RA and other autoimmune diseases by suppressing Foxp3 expression in Tregs via Bmi-1-mediated histone modification.

Keywords

Bmi-1; Foxp3; PI16; Regulatory T cells; Rheumatoid arthritis.

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