Protein neddylation and its role in health and diseases  

作　　者：Shizhen Zhang Qing Yu Zhijian Li Yongchao Zhao Yi Sun 

机构地区：[1]Department of Breast Surgery,the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310029,China [2]Cancer Institute(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310029,China [3]Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China [4]Department of Thyroid Surgery,Zhejiang Cancer Hospital,Institute of Basic Medicine and Cancer(IBMC),Chinese Academy of Sciences,Hangzhou 310022,China [5]Key Laboratory of Head&Neck Cancer Translational Research of Zhejiang Province,Hangzhou 310022,China [6]Department of Hepatobiliary and Pancreatic Surgery,Zhejiang University School of Medicine,Hangzhou 310029,China [7]Zhejiang Provincial Key Laboratory of Pancreatic Disease,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310029,China [8]Zhejiang University Cancer Center,Hangzhou 310029,China [9]Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang,Hangzhou 310024,China [10]Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University,Hangzhou 310053,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期1869-1904,共36页信号转导与靶向治疗（英文）

基　　金：This work was funded in part by the National Key R&D Program of China(grants 2022YFC3401500 to Y.S.and Y.Z.,and 2021YFA1101000 to Y.S.);the National Natural Science Foundation of China(grants 92253203 and U22A20317 to Y.S.,92053117 and 81972591 to Y.Z.,82202838 to S.Z.,and 82102749 to Q.Y.);Zhejiang Provincial Natural Science Foundation of China(grant LD22H300003 to Y.S.,LZ22H160003 to Y.Z.);Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(grant 2022R01002 to Y.S.).

摘　　要：NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin proteins.Neddylation of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular localization.Significantly,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among others.Thus,targeting neddylation becomes an attractive strategy for the treatment of these diseases.In this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates.We further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach.Finally,few perspectives were proposed for extensive future investigations.

关 键 词：NEDD8 ATTACHED ATTRACTIVE 

分 类 号：Q75[生物学—分子生物学]