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TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease
Yihui Li, … , Hao Wang, Ming Zhong
Yihui Li, … , Hao Wang, Ming Zhong
Published February 11, 2025
Citation Information: J Clin Invest. 2025;135(7):e175972. https://doi.org/10.1172/JCI175972.
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Research Article Cardiology Vascular biology Article has an altmetric score of 1

TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease

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Abstract

The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in ER stress in chronic kidney 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 homolog 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 KO 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 CKD.

Authors

Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong

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Figure 5

ATF4 and CHOP induced TRIB3 transcription in phosphorate stimuli.

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ATF4 and CHOP induced TRIB3 transcription in phosphorate stimuli.
(A) IG...
(A) IGV was used to display data for the TRIB3 loci, with ChIP-Seq tracks and sequence logo for ATF4 and CHOP. (B) Wild-type or mutant TRIB3 promoter luciferase plasmid. (C) (41.Luciferase activity of mVSMCs transfected with the TRIB3-WT or TRIB3-mut promoter luciferase plasmid and treated with Pi (2.6 mM) for 12 h or transfected with shRNA to knock down ATF4 or CHOP for 48 h). Statistical analyses were performed using 2-way ANOVA. ***P < 0.001, statistically significant vs. 1.TRIB3-WT without Pi treatment; †††P < 0.001, statistically significant vs. 4.transfected with shCTR and TRIB3-WT with Pi treatment. (D) ChIP-PCR showing enrichment of both ATF4 and CHOP at the TRIB3 binding site (BS) in mVSMCs treated Pi (2.6 mM) for 24 hours. Statistical analyses were performed using 1-way ANOVA. **P < 0.01, ***P < 0.001, statistically significant vs. 0 h Pi treatment (ATF4); ††P < 0.01, †††P < 0.001, statistically significant vs. 0 h Pi treatment (CHOP). (E and F) Formaldehyde-assisted isolation of regulatory elements–ChIP (FAIRE-ChIP) PCR was performed on Pi (2.6 mM) for indicated times in mVSMCs. Statistical analyses were performed using repeated measures 2-way ANOVA. (G–I) Representative Western blots of TRIB3, ATF4, and CHOP in mVSMCs treated with Pi (2.6 mM) at the indicated times after pretreatment with 4PBA 5 μM for 12 hours or transfection with shRNA for knockdown of ATF4 and CHOP for 48 hours. Statistical analyses were performed using repeated measures 2-way ANOVA. Data are shown in scatter dot plots and as the arithmetic mean ± SEM (AU). *P < 0.05, **P < 0.01, ***P < 0.001, statistically significant vs. 0 h treatment, DMSO, or shCTR. Each experiment was repeated independently 3–6 times. Data are shown in scatter dot plots and as the arithmetic mean ± SEM (AU).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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