Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1
Yidan Ma,
Xinxin Yuan,
Aodong Wei,
Xiaopeng Li,
Azim Patar,
Shaobo Su,
Songtao Wang,
Gaoen Ma,
Jiangli Zhu,
Eryan Kong
Affiliations
Yidan Ma
The 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
Xinxin Yuan
Sanquan College of Xinxiang Medical University, XinXiang 453003, Henan, China
Aodong Wei
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China
Xiaopeng Li
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China
Azim Patar
Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia
Shaobo Su
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China
Songtao Wang
Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453000, China
Gaoen Ma
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, China; Corresponding author. The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, China.
Jiangli Zhu
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041, China; Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and Major Human Diseases, Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Xinxiang Medical University, Xinxiang, 453000, China; Corresponding author. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041, China.
Eryan Kong
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and Major Human Diseases, Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Xinxiang Medical University, Xinxiang, 453000, China; Corresponding author. The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China.
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.
