title: Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.
abstract: Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down-regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation. Additionally, inactivation of neddylation promotes caspase dependent apoptosis of DCs. These phenomena were attributed to the inactivation of mTOR, which was caused by Cullin-1 deneddylation induced Deptor accumulation. Together, our findings revealed that neddylation inhibition suppressed DC functions through mTOR signaling pathway and provided a potential therapeutic opportunity in inflammatory bowel diseases.
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shurong
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhengting
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yaofei
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Sichang
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Maochen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism*; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D003517:Cyclopentanes; D016207:Cytokines; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011743:Pyrimidines; C570841:deptor protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; C539933:pevonedistat
keywords: Deptor; Immune response; Immunity; Immunology and Microbiology Section; dendritic cell; inflammatory bowel disease; mTOR; neddylation