[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-353301-105":59,"doc-detail-353301-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","protein-neddylation-as-a-therapeutic-target-challenges-and-opportunities","Protein neddylation as a therapeutic target - challenges and opportunities","","Protein neddylation is a conserved posttranslational conjugation that attaches NEDD8 to substrates through an E1–E2–E3 enzyme cascade. Dysregulated neddylation contributes to diverse diseases, especially cancer, making it a promising therapeutic target. This Review summarizes neddylation biochemistry, biological roles, disease-associated alterations, and validation for cancer therapy, including discovery of inhibitors and critical assessment of MLN4924 (pevonedistat) and TAS4464 clinical trial progress.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/protein-neddylation-as-a-therapeutic-target-challenges-and-opportunities/353301/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/protein-neddylation-as-a-therapeutic-target-challenges-and-opportunities/353301.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-26","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is protein neddylation and how does it work at the molecular level?","Question",{"text":112,"@type":113},"Protein neddylation conjugates NEDD8 to substrates via a three-enzyme cascade involving an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase, forming and transferring catalytic thioester intermediates.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does neddylation differ from ubiquitylation in its main biological outcomes?",{"text":117,"@type":113},"Although both use similar E1–E2–E3 machinery, ubiquitylation commonly drives proteasomal degradation or functional shifts via different linkage types, while neddylation primarily affects substrate localization, stability, and function.",{"name":119,"@type":110,"acceptedAnswer":120},"Which deneddylases reverse neddylation, and what roles do CSN and SENP8 play?",{"text":121,"@type":113},"Deneddylation is catalyzed by deneddylases including the COP9 signalosome (CSN) and SENP8. CSN is described as a major deneddylase removing NEDD8 from cullin and noncullin substrates, while SENP8 shows high specificity for NEDD8 on noncullin proteins.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},353301,1790165129,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","The Journal of Clinical Investigation REVIEW  \nProtein neddylation as a therapeutic target: challengesand opportunities  \nShizhen Zhang,1,2 Huiyin Lan,3 and Yi Sun1,4,5,6,7  \n1Cancer Institute and 2Department of Breast Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 3Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, China. 4Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. 5Zhejiang University Cancer Center, Hangzhou, China. 6Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, China. 7State Key Laboratory of Transvascular Implantation Devices, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.  \nProtein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challengesand emerging opportunities for therapeutic strategies targeting neddylation.  \nIntroduction  \nNeddylation is an evolutionarily conserved posttranslational modification that conjugates the ubiquitin-like protein neural precursor cell–expressed developmentally downregulated protein 8 (NEDD8) to target substrates (1) . Neddylation is structurally and mechanistically similar to ubiquitylation, with both modifications employing a three-enzyme cascade of E1-activating, E2-conjugating, and E3 ligase enzymes. However, key differences exist: ubiquitylation primarily drives substrate for proteasomal degradation via K48-linked chains or alters substrate functions through the K63 linkage, whereas neddylation mainly alters the subcellular localization, stability, and function of its substrates (2, 3) .  \nThe neddylation modification begins with ATP-dependent activation of NEDD8 by the E1 enzyme Nedd8-activating enzyme (NAE, an NAE1-UBA3 heterodimer), forming a thioester bond. NEDD8 is then transferred to the catalytic cysteine of an E2 enzyme (UBE2M or UBE2F) . Finally, an E3 ligase (e.g. , RBX1 or RBX2) mediates the transfer of NEDD8 to a lysine residue on the substrates, which include cullins and noncullin proteins (4, 5) . In addition, the scaffold-type E3 ligases defective in cullin neddylation 1–5 (DCN1–DCN5) cooperate with RBX1 or RBX2 to facilitate cullin neddylation (6) .  \nThe reverse process is deneddylation, which is catalyzed by deneddylases, including the COP9 signalosome (CSN), sentrin-specific protease 8 (SENP8, also known as DEN1 or NEDP1), ataxin-3, ubiquitin-specific peptidase 21 (USP21), and ubiquitin  \nAuthorship note: SZ and HL contributed equally to this work.  \nCopyright: © 2026, Zhang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nReference information: J Clin Invest. 2026;136(15):e206924 .  \n[https://doi.org/10.1172/JCI206924](https://doi.org/10.1172/JCI206924) .  \nC-terminal hydrolase L3 (UCH-L3) (3, 4) . The CSN complex is the major deneddylase, cleaving NEDD8 from both cullin and noncullin substrates (7) . It binds tightly to deneddylated cullin-RING ligases (CRLs), sterically hindering ","cbCairDoWJSeiwPr","https://ap.wps.com/l/cbCairDoWJSeiwPr","pdf",1739334,14,"English","# Introduction\n## Neddylation cascade and comparison with ubiquitylation\n## Enzymatic cycle: neddylation and deneddylation\n## Physiological substrates and functional consequences\n## Therapeutic targeting: inhibitors and clinical trials\n## Challenges and emerging opportunities","[{\"question\":\"What is protein neddylation and how does it work at the molecular level?\",\"answer\":\"Protein neddylation conjugates NEDD8 to substrates via a three-enzyme cascade involving an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase, forming and transferring catalytic thioester intermediates.\"},{\"question\":\"How does neddylation differ from ubiquitylation in its main biological outcomes?\",\"answer\":\"Although both use similar E1–E2–E3 machinery, ubiquitylation commonly drives proteasomal degradation or functional shifts via different linkage types, while neddylation primarily affects substrate localization, stability, and function.\"},{\"question\":\"Which deneddylases reverse neddylation, and what roles do CSN and SENP8 play?\",\"answer\":\"Deneddylation is catalyzed by deneddylases including the COP9 signalosome (CSN) and SENP8. CSN is described as a major deneddylase removing NEDD8 from cullin and noncullin substrates, while SENP8 shows high specificity for NEDD8 on noncullin proteins.\"}]","Protein neddylation as a therapeutic target - challenges and opportunities | PDF",1790104588,35]