AI Article Synopsis
- - The study investigates the role of Speckle-type pox virus and zinc finger protein (SPOP) in cardiac fibrosis using TGF-β1 to activate cardiac fibroblasts and a mouse model of myocardial infarction (MI).
- - SPOP levels increased in both fibrotic hearts and treated fibroblasts, where higher SPOP promoted myofibroblast transformation and worsened cardiac fibrosis, while lower levels had the opposite effect.
- - Mechanistically, SPOP leads to the degradation of the RACK1 protein, which activates cardiac fibroblasts, suggesting that targeting SPOP and RACK1 could offer new treatments for fibrosis-related heart diseases.
Article Abstract
Speckle-type pox virus and zinc finger (POZ) protein (SPOP), a substrate recognition adaptor of cullin-3 (CUL3)/RING-type E3 ligase complex, is investigated for its role in cardiac fibrosis in our study. Cardiac fibroblasts (CFs) activation was achieved with TGF-β1 (20 ng/mL) and MI mouse model was established by ligation of the left anterior descending coronary, and lentivirus was employed to mediate interference of SPOP expression. SPOP was increased both in fibrotic post-MI mouse hearts and TGF-β1-treated CFs. The gain-of-function of SPOP promoted myofibroblast transformation in CFs, and exacerbated cardiac fibrosis and cardiac dysfunction in MI mice, while the loss-of-function of SPOP exhibited the opposite effects. Mechanistically, SPOP bound to the receptor of activated protein C kinase 1 (RACK1) and induced its ubiquitination and degradation by recognizing Ser/Thr-rich motifs on RACK1, leading to Smad3-mediated activation of CFs. Forced RACK1 expression canceled the effects of SPOP on cardiac fibrosis. The study reveals therapeutic targets for fibrosis-related cardiac diseases.
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| http://dx.doi.org/10.1016/j.chembiol.2023.06.015 | DOI Listing |
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