1. Academic Validation
  2. TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease

TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease

  • J Clin Invest. 2025 Feb 11:e175972. doi: 10.1172/JCI175972.
Yihui Li 1 Chang Ma 1 Yanan Sheng 1 Shanying Huang 1 Huaibing Sun 2 Yun Ti 1 Zhihao Wang 3 Feng Wang 4 Fangfang Chen 5 Chen Li 6 Haipeng Guo 6 Mengxiong Tang 7 Fangqiang Song 8 Hao Wang 6 Ming Zhong 1
Affiliations

Affiliations

  • 1 State Key Laboratory for Innovation and Transformation of Luobing Theory, D, Qilu Hospital of Shandong University, Jinan, China.
  • 2 Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, China.
  • 3 Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China.
  • 4 Department of Critical Care Medicine, Shandong Provincial Hospital, Jinan, China.
  • 5 Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China.
  • 6 Department of Critical Care Medicine, Qilu Hospital; Innovation Research Ce, Shandong University, Jinan, China.
  • 7 Department of Emergency, Qilu Hospital of Shandong University, Jinan, China.
  • 8 Department of Critical Care Medicine, The Affiliated Tengzhou Hospital of Xuzhou Medical University/ Tengzhou Central People's Hospital, Xuzhou, China.
Abstract

The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in endoplasmic reticulum (ER) stress in chronic renal disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein Ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX Family Transcription Factor 2 (Runx2) and Smad Family Member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic knockout of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for chronic renal disease.

Keywords

Cardiology; Cardiovascular disease; Ubiquitin-proteosome system; Vascular biology.

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