Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system  

作　　者：Yanli Chang Jiangli Zhu Xiaopeng Li Yi Deng Birou Lai Yidan Ma Jia Tong Huicong Liu Juanjuan Li Chenyu Yang Qiao Chen Chengbiao Lu Yinming Liang Shiqian Qi Xiaoning Wang Eryan Kong 

机构地区：[1]The Third Affiliated Hospital of Xinxiang Medical University,Xinxiang,China [2]Institute of Psychiatry and Neuroscience,Xinxiang Key Laboratory of Protein Palmitoylation and Major Human Diseases,Xinxiang Medical University,Xinxiang,China [3]Department of Urology,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University and National Collaborative Innovation Center,Chengdu,China [4]Center of Cryo-Electron Microscopy,Zhejiang University,Hangzhou,China [5]Department of Nutrition,Third Medical Center of PLA General Hospital,Beijing,China [6]School of Life Sciences,Fudan University,Shanghai,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第10期4683-4699,共17页信号转导与靶向治疗（英文）

基　　金：National Natural Science Foundation of China(Grant No.32100776 to Y.L.C.,and No.32371309 to E.Y.K.);The genetic modification of cell lines and mouse were supported by 111 program(D20036).

摘　　要：The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

关 键 词：MYELIN SYSTEM TOGETHER 

分 类 号：R741[医药卫生—神经病学与精神病学]