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Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1
Yidan Ma1, Xinxin Yuan2, Aodong Wei3
1The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia.
Abstract:
The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.
Insights
Protein S-palmitoylation, particularly of Gpx1, influences angiogenesis. Inhibiting depalmitoylation via PPT1 enhances blood vessel growth, offering a therapeutic target for angiogenesis-related diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Protein S-palmitoylation's role in angiogenesis is understudied.
- Gpx1 (Glutathione peroxidase 1) is identified as a palmitoylated protein.
- Understanding Gpx1 palmitoylation may reveal new pathological mechanisms in angiogenesis.
Purpose of the Study:
- To investigate the role of Gpx1 palmitoylation in angiogenesis.
- To elucidate the involvement of PPT1 (Palmitoyl-protein thioesterase 1) in Gpx1 depalmitoylation and its impact on angiogenesis.
- To explore the therapeutic potential of targeting the PPT1-Gpx1 axis in angiogenesis.
Main Methods:
- Investigated Gpx1 palmitoylation sites (Cys-76, Cys-113) and PPT1's role in depalmitoylation.
- Assessed the impact of Gpx1 palmitoylation status and PPT1 activity on neovascular angiogenesis in vitro and in vivo.
- Utilized an Oxygen-Induced Retinopathy (OIR) mouse model to study pathological angiogenesis.
Main Results:
- Gpx1 is palmitoylated at Cys-76 and -113; PPT1 regulates its depalmitoylation, affecting protein stability.
- Inhibition of Gpx1 palmitoylation or increased PPT1 expression enhances angiogenesis.
- PPT1 deficiency attenuates angiogenesis in the OIR model.
- Hypoxia reduces Gpx1 palmitoylation; inhibiting PPT1 with DC661 suppresses retinal angiogenesis in OIR.
Conclusions:
- Protein palmitoylation is critical in regulating angiogenesis.
- The PPT1-Gpx1 axis represents a novel mechanism controlling angiogenesis.
- Targeting PPT1 offers a potential therapeutic strategy for managing angiogenesis-related conditions.
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