title: Neddylation plays an important role in the regulation of murine and human dendritic cell function.
abstract: Posttranslational protein modifications (PTMs) are necessary for cells to function properly. The role of PTMs in regulating immune responses, specifically those mediated by dendritic cells (DCs), which are critical for both innate and adaptive immunity, is not well understood. Utilizing multiple but complementary approaches, we determined the role of an important but less understood type of PTM, namely, neddylation, in regulating DC functions. Inhibition of neddylation suppressed the release of proinflammatory cytokines by DCs in response to Toll-like receptor, nucleotide oligomerization domain-like receptor, and noninfectious CD40L stimulation. These effects were more profound than those mediated by the proteasome inhibitor bortezomib or a commonly used antiinflammatory agent, dexamethasone. Targeting neddylation also suppressed the ability of DCs to stimulate murine allogeneic T cells in vitro and in vivo and human allogeneic T-cell responses in vitro. Mechanistic studies demonstrated that inhibition of neddylation reduced both canonical and noncanonical nuclear factor-κB (NF-κB) activity. Neddylation inhibition prevented the degradation of inhibitor-κB and thus reduced the translocation and activation of NF-κB, but without perturbation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Thus, blocking neddylation could be a novel strategy for mitigating immune-mediated disease processes.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; and.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Steven
authors.initials: S
authors.lastname: Kapeles
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.forename: Hiroya
authors.initials: H
authors.lastname: Tamaki
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hou
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000075687:NEDD8 Protein; D016328:NF-kappa B; D010641:Phenotype; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014452:Ubiquitins / Q000819:agonists / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003517:Cyclopentanes; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; C513172:Nedd8 protein, mouse; D011743:Pyrimidines; C573100:SAG protein, mouse; D014452:Ubiquitins; D044844:beta-Transducin Repeat-Containing Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; C539933:pevonedistat