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

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外文摘要：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.

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

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作者单位：

The Third Affiliated Hospital of Xinxiang Medical University,Xinxiang,China

Institute of Psychiatry and Neuroscience,Xinxiang Key Laboratory of Protein Palmitoylation and Major Human Diseases,Xinxiang Medical University,Xinxiang,China

Department of Urology,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital Sichuan University and National Collaborative Innovation Center,Chengdu,China

Center of Cryo-Electron Microscopy,Zhejiang University,Hangzhou,China

Department o Nutrition,Third Medical Center of PLA General Hospital,Beijing,China

School of Life Sciences,Fudan University,Shanghai,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of Chinagenetic modification of cell lines and mouse were supported by 111 program

项目编号：

3210077632371309D20036

出版年：

2024

DOI：

10.1038/s41392-024-01971-5

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(10)