Diverse and pivotal roles of neddylation in metabolism and immunity

Neddylation is one type of protein post‐translational modification by conjugating a ubiquitin‐like protein neural precursor cell‐expressed developmentally downregulated protein 8 to substrate proteins via a cascade involving E1, E2, and E3 enzymes. The best‐characterized substrates of neddylation are cullins, essential components of cullin‐RING E3 ubiquitin–ligase complexes. The discovery of noncullin neddylation targets indicates that neddylation may have diverse biological functions. Indeed, neddylation has been implicated in various cellular processes including cell cycle progression, metabolism, immunity, and tumorigenesis. Here, we summarized the reported neddylation substrates and also discuss the functions of neddylation in the immune system and metabolism.

• Publication year

  2020

• Venue

  The FEBS Journal

• Publication date

  2020-10-06

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1111/febs.15584PMID 33025631
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• An integrative gene expression microarray meta-analysis identifies host factors and key signatures involved in Hepatitis B Virus infection.

  2020cited by this paper
• Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome

  2020cited by this paper
• Lipin-2 degradation elicits a proinflammatory gene signature in macrophages.

  2020cited by this paper
• Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics

  2020cited by this paper
• Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid β-oxidation

  2020cited by this paper
• Neddylation-mediated Nedd4-2 activation regulates ubiquitination modification of renal NBCe1.

  2020cited by this paper
• Pathogenic Bacteria

  2020cited by this paper
• Neddylation-Independent Activities of MLN4924.

  2020cited by this paper
• Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells

  2020cited by this paper
• The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity.

  2020cited by this paper
• Quantification of exercise‐regulated ubiquitin signaling in human skeletal muscle identifies protein modification cross talk via NEDDylation

  2020cited by this paper
• Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment

  2020cited by this paper
• Old and New Concepts in Ubiquitin and NEDD8 Recognition

  2020cited by this paper
• Neddylation: a novel modulator of the tumor microenvironment

  2019cited by this paper
• Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.

  2019cited by this paper
• TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation

  2019cited by this paper
• Aryl hydrocarbon receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARγ for proteasomal degradation

  2019cited by this paper
• Nedd8 hydrolysis by UCH proteases in Plasmodium parasites

  2019cited by this paper
• Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

  2019cited by this paper
• Proteomic profiling of HIV-1 infection of human CD4+ T cells identifies PSGL-1 as an HIV restriction factor

  2019cited by this paper
• Inhibition of neddylation plays protective role in lipopolysaccharide-induced kidney damage through CRL-mediated NF-κB pathways.

  2019cited by this paper
• Neddylation Facilitates the Antiviral Response in Zebrafish

  2019cited by this paper
• Anticancer drug discovery by targeting cullin neddylation

  2019cited by this paper
• Adenovirus oncoprotein E4orf6 triggers Cullin5 neddylation to activate the CLR5 E3 ligase for p53 degradation.

  2019cited by this paper
• Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

  2019cited by this paper
• Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

  2019cited by this paper
• MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury

  2019cited by this paper
• Degradation of splicing factor SRSF3 contributes to progressive liver disease.

  2019cited by this paper
• CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity

  2019cited by this paper
• Salmonella Effector SteA Suppresses Proinflammatory Responses of the Host by Interfering With IκB Degradation

  2019cited by this paper
• NEDDylation regulates RAD18 ubiquitination and localization in response to oxidative DNA damage.

  2019cited by this paper
• MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling.

  2019cited by this paper
• Inhibition of neddylation pathway represses influenza virus replication and pro-inflammatory responses.

  2018cited by this paper
• Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila.

  2018cited by this paper
• Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

  2018cited by this paper
• The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src

  2018cited by this paper
• CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis

  2018cited by this paper
• MLN4924 suppresses lipopolysaccharide-induced proinflammatory cytokine production in neutrophils in a dose-dependent manner.

  2018cited by this paper
• A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells.

  2018cited by this paper
• βTrCP is Required for HIV-1 Vpu Modulation of CD4, GaLV Env, and BST-2/Tetherin

  2018cited by this paper
• SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets

  2018cited by this paper
• Proteasome lid bridges mitochondrial stress with Cdc53/Cullin1 NEDDylation status

  2018cited by this paper
• Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression.

  2018cited by this paper
• NEDD8-its role in the regulation of Cullin-RING ligases.

  2018cited by this paper
• UBE2M Is a Stress-Inducible Dual E2 for Neddylation and Ubiquitylation that Promotes Targeted Degradation of UBE2F.

  2018cited by this paper
• All-trans retinoic acid induces autophagic degradation of ubiquitin-like modifier activating enzyme 3 in acute promyelocytic leukemia cells

  2018cited by this paper
• Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

  2018cited by this paper
• Inhibition of neddylation ameliorates DSS-induced colitis

  2018cited by this paper
• Ajuba inhibits hepatocellular carcinoma cell growth via targeting of β-catenin and YAP signaling and is regulated by E3 ligase Hakai through neddylation

  2018cited by this paper
• The NEDD8 E3 ligase DCNL5 is phosphorylated by IKK alpha during Toll-like receptor activation

  2018cited by this paper
• Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

  2017cited by this paper
• Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice.

  2017cited by this paper
• HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

  2017cited by this paper
• Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

  2017cited by this paper
• NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage

  2017cited by this paper
• A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease.

  2017cited by this paper
• 20-Hydroxyeicosatetraenoic acid regulates the expression of Nedd4‑2 in kidney and liver through a neddylation modification pathway.

  2017cited by this paper
• The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis

  2017cited by this paper
• Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes

  2017cited by this paper
• A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation

  2017cited by this paper
• NEDDylation of PB2 Reduces Its Stability and Blocks the Replication of Influenza A Virus

  2017cited by this paper
• MLN4924 protects against bleomycin-induced pulmonary fibrosis by inhibiting the early inflammatory process.

  2017cited by this paper
• Neddylated Cullin 3 is required for vascular endothelial‐cadherin‐mediated endothelial barrier function

  2017cited by this paper
• Shutdown of interferon signaling by a viral-hijacked E3 ubiquitin ligase

  2017cited by this paper
• Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation

  2017cited by this paper
• Deregulated neddylation in liver fibrosis

  2017cited by this paper
• Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury.

  2017cited by this paper
• MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination.

  2017cited by this paper
• Cul3 neddylation is crucial for gradual lipid droplet formation during adipogenesis.

  2017cited by this paper
• NEDDylation promotes stress granule assembly

  2016cited by this paper
• The antiobesity factor WDTC1 suppresses adipogenesis via the CRL4WDTC1 E3 ligase

  2016cited by this paper
• Itch promotes the neddylation of JunB and regulates JunB-dependent transcription.

  2016cited by this paper
• SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses.

  2016cited by this paper
• Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation

  2016cited by this paper
• MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

  2016cited by this paper
• A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma

  2016cited by this paper
• Nedd8 targets ubiquitin ligase Smurf2 for neddylation and promote its degradation.

  2016cited by this paper
• The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation

  2016cited by this paper
• Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

  2016cited by this paper
• PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

  2016cited by this paper
• Cullin3–KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression

  2016cited by this paper
• Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome

  2016cited by this paper
• Hepatitis B Virus X Protein Promotes Degradation of SMC5/6 to Enhance HBV Replication.

  2016cited by this paper
• Lack of CUL4B in Adipocytes Promotes PPARγ-Mediated Adipose Tissue Expansion and Insulin Sensitivity

  2016cited by this paper
• Protein Kinase R Degradation Is Essential for Rift Valley Fever Virus Infection and Is Regulated by SKP1-CUL1-F-box (SCF)FBXW11-NSs E3 Ligase

  2016cited by this paper
• Broad and potent antiviral activity of the NAE inhibitor MLN4924

  2016cited by this paper
• Neddylation controls basal MKK7 kinase activity in breast cancer cells

  2016cited by this paper
• Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation*

  2016cited by this paper
• Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation

  2016cited by this paper
• T cell exclusion, immune privilege, and the tumor microenvironment

  2015cited by this paper
• Stabilization of HIF through inhibition of Cullin‐2 neddylation is protective in mucosal inflammatory responses

  2015cited by this paper
• HIV-1 Vpu utilizes both cullin-RING ligase (CRL) dependent and independent mechanisms to downmodulate host proteins

  2015cited by this paper
• CAND1 exchange factor promotes Keap1 integration into cullin 3-RING ubiquitin ligase during adipogenesis.

  2015cited by this paper
• NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target

  2015cited by this paper
• Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

  2015cited by this paper
• Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors

  2015cited by this paper
• Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

  2015cited by this paper
• Suppressive role of neddylation in dendritic cells during Mycobacterium tuberculosis infection.

  2015cited by this paper
• The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis

  2015cited by this paper
• Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer

  2015cited by this paper

• Progression on Mechanism and Therapeutic Implications of Neddylation in Lung Cancer

  2026cites this paper
• Neddylation Targets and Stabilizes NLRP3 to Augment Inflammasome-Mediated Colitis and Mood Disorder.

  2026cites this paper
• Post-translational modification gene signatures implicate FBXW7 in immune and vascular dysregulation of Moyamoya disease

  2025cites this paper
• NEDD8-specific protease 1 deficiency as a novel driver of hepatoblastoma development through dysregulation of the CAND1-NEDD8 pathway.

  2025cites this paper
• Neonatal Liver‐Specific UBA3 Deficiency Leads to TNF‐α‐Dependent Necroptosis of Liver Sinusoidal Endothelial Cells During Cyst Formation

  2025cites this paper
• Lysine: Sources, Metabolism, Physiological Importance, and Use as a Supplement

  2025cites this paper
• Increased glucose utilization is a targetable vulnerability to overcome drug resistance associated with neddylation blockade.

  2025cites this paper
• TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation

  2025cites this paper
• The ubiquitin conjugating enzyme E2 F (UBE2F)-RING-box protein 2 (RBX2)-mediated neddylation of Cullin5 facilitates pseudorabies virus replication.

  2025cites this paper
• Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

  2024cites this paper
• Attenuating Cartilage Degeneration in a Low Mechanical Compression Rat Model Through Intra-Articular Injections of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells.

  2024cites this paper
• Upregulation of Cullin1 neddylation promotes glycolysis and M1 polarization of macrophage via NF-κB p65 pathway in sepsis

  2024cites this paper
• Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling.

  2024cites this paper
• LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Cerebral Organoids

  2024cites this paper
• Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

  2024cites this paper
• Proteome changes in larval zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) exposed to (±) anatoxin-a.

  2024cites this paper
• Etoposide-induced SENP8 confers a feed-back drug resistance on acute lymphoblastic leukemia cells

  2024cites this paper
• Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

  2024cites this paper
• SUMOylation and related post-translational modifications in natural killer cell anti-cancer responses

  2023cites this paper
• MLN4924 Promotes Self-Renewal of Limbal Stem Cells and Ocular Surface Restoration

  2023cites this paper
• Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives

  2023cites this paper
• NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells

  2023cites this paper
• Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions

  2023cites this paper
• Pevonedistat, a First in-class NEDD8-activating Enzyme Inhibitor, sensitizes cancer cells to VSVΔ51 Oncolytic Virotherapy.

  2023cites this paper
• Effects of neddylation on viral infection: an overview

  2023cites this paper
• Transcriptomic response to ISAV infection in the gills, head kidney and spleen of resistant and susceptible Atlantic salmon

  2022cites this paper
• Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

  2022cites this paper
• Stress - Regulation of SUMO conjugation and of other Ubiquitin-Like Modifiers.

  2022cites this paper
• Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients

  2022cites this paper
• Neddylation Inhibition Causes Impaired Mouse Embryo Quality and Blastocyst Hatching Failure Through Elevated Oxidative Stress and Reduced IL-1β

  2022cites this paper
• Protein post-translational modifications in the regulation of cancer hallmarks

  2022cites this paper
• Structural changes of proteins in liver cirrhosis and consequential changes in their function

  2022cites this paper
• Effects of Hyperoxia and Hyperoxic Oscillations on the Proteome of Murine Lung Microvascular Endothelium

  2022cites this paper
• Post-translational Modifications in Brain Diseases: A Future for Biomarkers.

  2022cites this paper
• SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone

  2022cites this paper
• A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy

  2022cites this paper
• Recycling and Reshaping—E3 Ligases and DUBs in the Initiation of T Cell Receptor-Mediated Signaling and Response

  2022cites this paper
• The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma

  2021cites this paper
• Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

  2021cites this paper
• LZTR1: A promising adaptor of the CUL3 family

  2021cites this paper
• Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells

  2021cites this paper
• Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in Dictyostelium discoideum

  2021cites this paper
• Siah1 in cancer and nervous system diseases (Review).

  2021cites this paper
• How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity

  2021cites this paper
• The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

  2021cites this paper
• Widespread Alternative Splicing Changes in Metastatic Cells.

  2021cites this paper
• Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses

  2021cites this paper
• Ubiquitin pathways regulate the pathogenesis of chronic liver disease.

  2021cites this paper
• LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Brain Organoids

  year unknowncites this paper