S-Nitrosylation-mediated coupling of DJ-1 with PTEN induces PI3K/AKT/mTOR pathway-dependent keloid formation  

作　　者：Dongming Lv Zhongye Xu Pu Cheng Zhicheng Hu Yunxian Dong Yanchao Rong Hailin Xu Zhiyong Wang Xiaoling Cao Wuguo Deng Bing Tang 

机构地区：[1]Department of Burn and Plastic Surgery,the First Affiliated Hospital of Sun Yat-sen University,58 Zhongshan Road II,Guangzhou 510080,China [2]Department of General Surgery,the Seventh Affiliated Hospital of Sun Yat-sen University,628 Zhenyuan Road,Shenzhen,China [3]Department of Plastic Surgery,Guangdong Second Provincial General Hospital,Southern Medical University,466 Xingang Middle Road,Guangzhou,China [4]Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Collaborative Innovation Center of Cancer Medicine,651 Dongfeng East Road,Guangzhou,China

出　　处：《Burns & Trauma》2023年第1期536-549,共14页烧伤与创伤（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(No.82272273,No.82072181,No.81871565,No.81571908);the Sun Yat-sen University Clinical Research 5010 Program(No.2018003).

摘　　要：Background:Keloids are aberrant dermal wound healing characterized by invasive growth,extracellular matrix deposition,cytokine overexpression and easy recurrence.Many factors have been implicated as pathological causes of keloids,particularly hyperactive inflammation,tension alignment and genetic predisposition.S-Nitrosylation(SNO),a unique form of protein modification,is associated with the local inflammatory response but its function in excessive fibrosis and keloid formation remains unknown.We aimed to discover the association between protein SNO and keloid formation.Methods:Normal and keloid fibroblasts were isolated from collected normal skin and keloid tissues.The obtained fibroblasts were cultured in DMEM supplemented with 10%fetal bovine serum and 1%penicillin/streptomycin.The effects of DJ-1 on cell proliferation,apoptosis,migration and invasion,and on the expression of proteins were assayed.TurboID-based proximity labelling and liquid chromatography-mass spectrometry were conducted to explore the potential targets of DJ-1.Biotin-switch assays and transnitrosylation reactions were used to detect protein SNO.Quantitative data were compared by two-tailed Student’s t test.Results:We found that DJ-1 served as an essential positive modulator to facilitate keloid cell proliferation,migration and invasion.A higher S-nitrosylated DJ-1(SNO-DJ-1)level was observed in keloids,and the effect of DJ-1 on keloids was dependent on SNO of the Cys106 residue of the DJ-1 protein.SNO-DJ-1 was found to increase the level of phosphatase and tensin homolog(PTEN)S-nitrosylated at its Cys136 residue via transnitrosylation in keloids,thus diminishing the phosphatase activity of PTEN and activating the PI3K/AKT/mTOR pathway.Furthermore,Cys106-mutant DJ-1 is refractory to SNO and abrogates DJ-1-PTEN coupling and the SNO of the PTEN protein,thus repressing the PI3K/AKT/mTOR pathway and alleviating keloid formation.Importantly,the biological effect of DJ-1 in keloids is dependent on the SNO-DJ-1/SNO-PTEN/PI3K/AKT/mTOR axis.Conclusi

关 键 词：DJ-1 PTEN Protein S-nitrosylation Transnitrosylation KELOID S-NITROSYLATION 

分 类 号：R619.2[医药卫生—外科学]