Activation of noncanonical NF-κB requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2, TRAF3 and the kinase NIK

Recent studies suggest that nuclear factor κB-inducing kinase (NIK) is suppressed through constitutive proteasome-mediated degradation regulated by TRAF2, TRAF3 and cIAP1 or cIAP2. Here we demonstrated that the degradation of NIK occurs upon assembly of a regulatory complex through TRAF3 recruitment of NIK and TRAF2 recruitment of cIAP1 and cIAP2. In contrast to TRAF2 and TRAF3, cIAP1 and cIAP2 seem to play redundant roles in the degradation of NIK, as inhibition of both cIAPs was required for noncanonical NF-κB activation and increased survival and proliferation of primary B lymphocytes. Furthermore, the lethality of TRAF3 deficiency in mice could be rescued by a single NIK gene, highlighting the importance of tightly regulated NIK.

• Publication year

  2008

• Venue

  Nature Immunology

• Publication date

  2008-11-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ni.1676PMID 18997794PMCID 2676931
• 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.

• Cutting-Edge Apoptosis-Based Therapeutics

  2012cited by this paper
• Control of canonical NF-κB activation through the NIK–IKK complex pathway

  2008cited by this paper
• Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling Complex

  2008cited by this paper
• TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor.

  2008cited by this paper
• Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.

  2007cited by this paper
• The inhibitors of apoptosis (IAPs) as cancer targets

  2007cited by this paper
• Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

  2007cited by this paper
• IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

  2007cited by this paper
• IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.

  2007cited by this paper
• Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway.

  2007cited by this paper
• Constitutive NF-KB activation, enhanced granulopoiesis, and neonatal lethality in IKB~-deficient mice

  2007cited by this paper
• A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.

  2007cited by this paper
• Rescue of TRAF3-null mice by p100 NF-κB deficiency

  2006cited by this paper
• Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival

  2006cited by this paper
• Specificity of TRAF3 in Its Negative Regulation of the Noncanonical NF-κB Pathway*

  2006cited by this paper
• BAFF costimulation of Toll‐like receptor‐activatedB‐1 cells

  2006cited by this paper
• Ten years after…

  2006cited by this paper
• Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif

  2006cited by this paper
• The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development.

  2006cited by this paper
• Differential Regulation of CD40-Mediated TNF Receptor-Associated Factor Degradation in B Lymphocytes1

  2005cited by this paper
• Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo

  2005cited by this paper
• The two NF-κB activation pathways and their role in innate and adaptive immunity

  2004cited by this paper
• TRAF3 Forms Heterotrimers with TRAF2 and Modulates Its Ability to Mediate NF-κB Activation*

  2004cited by this paper
• The two NF-kappaB activation pathways and their role in innate and adaptive immunity.

  2004cited by this paper
• Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers

  2004cited by this paper
• Regulation of the NF-κB-inducing Kinase by Tumor Necrosis Factor Receptor-associated Factor 3-induced Degradation*

  2004cited by this paper
• A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death.

  2004cited by this paper
• A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death

  2004cited by this paper
• TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells.

  2004cited by this paper
• TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation.

  2004cited by this paper
• Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers.

  2004cited by this paper
• CD40 regulates the processing of NF-kappaB2 p100 to p52.

  2002cited by this paper
• BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells

  2002cited by this paper
• CD40 regulates the processing of NF‐κB2 p100 to p52

  2002cited by this paper
• BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells.

  2002cited by this paper
• Cloning and characterization of the rat homologues of the Inhibitor of Apoptosis protein 1, 2, and 3 genes.

  2002cited by this paper
• Regulation of TRAF2 Signaling by Self-induced Degradation*

  2002cited by this paper
• Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice

  2001cited by this paper
• Differential Signaling and Tumor Necrosis Factor Receptor–Associated Factor (Traf) Degradation Mediated by Cd40 and the Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 (Lmp1)

  2001cited by this paper
• Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice.

  2001cited by this paper
• Essential role of nuclear factor(NF)-κB-inducing kinase and inhibitor of κB(IκB)kinase α in NF-κB activation through lymphotoxin β receptor,but not through tumor necrosis factor receptor 1

  2001cited by this paper
• Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase.

  1999cited by this paper
• Bridging the Gap: Composition, Regulation, and Physiological Function of the IκB Kinase Complex

  1999cited by this paper
• Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase

  1999cited by this paper
• An Intact Zinc Ring Finger Is Required for Tumor Necrosis Factor Receptor-associated Factor-mediated Nuclear Factor-κB Activation but Is Dispensable for c-Jun N-terminal Kinase Signaling*

  1998cited by this paper
• Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2.

  1997cited by this paper
• MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1

  1997cited by this paper
• Osteopetrosis in mice lacking NF-κB1 and NF-κB2

  1997cited by this paper
• NF-kappa B: ten years after.

  1996cited by this paper
• Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses.

  1996cited by this paper
• NF-κB: Ten Years After

  1996cited by this paper
• The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.

  1995cited by this paper
• Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice.

  1995cited by this paper
• Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses.

  1995cited by this paper
• NF-kappa B and rel proteins in innate immunity.

  1995cited by this paper
• Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses

  1995cited by this paper
• Clonal lymphoid progenitor cell lines expressing the BCR/ABL oncogene retain full differentiative function.

  1990cited by this paper

• Epstein-barr virus latent membrane protein 1 targets cIAP1, cIAP2 and TRAF2 for proteasomal degradation to activate the non-canonical NF-κB pathway

  2026cites this paper
• The NF-κB-inducing kinase: a central regulator of immunity and autoimmune diseases

  2026cites this paper
• Epstein-Barr Virus Latent Membrane Protein 1 targets cIAP1, cIAP2 and TRAF2 for Proteasomal Degradation to Activate the Non-canonical NF-κB Pathway

  2025cites this paper
• Targeting NF-κB-inducing kinase (NIK) in the non-canonical pathway: Advances in the development of NIK inhibitors.

  2025cites this paper
• Xevinapant plus avelumab in advanced solid tumours, with a dose expansion in advanced non-small-cell lung cancer: exploratory biomarker, safety and efficacy analyses from an open-label, nonrandomised phase Ib study

  2025cites this paper
• Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection

  2025cites this paper
• HSP47 inhibition-induced CD155 expression through TRAF2 deubiquitination promotes tumor immune evasion

  2025cites this paper
• TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors

  2025cites this paper
• Targeting the inhibitors of apoptosis proteins (IAPs) to combat drug resistance in cancers

  2025cites this paper
• TRAF2 mediates Wnt-induced β-catenin nuclear translocation by associating with the nuclear pore complex.

  2025cites this paper
• Second Mitochondrial Activator of Caspases Mimetics Accelerate Progression of Locally Advanced Head and Neck Cancer.

  2025cites this paper
• SMAC mimetics induce human macrophages to phagocytose live cancer cells

  2025cites this paper
• NF-κB: master regulator of cellular responses in health and disease

  2025cites this paper
• Ubiquitin and ubiquitin-like proteins in HPV-driven carcinogenesis

  2025cites this paper
• Targeting anti-apoptotic mechanisms in tumour cells: Strategies for enhancing Cancer therapy.

  2025cites this paper
• Reduction of TRAF3 by heterozygosity or aging impacts B cell function

  2025cites this paper
• Monogenic disorders of the TNF signalling pathway

  2025cites this paper
• NF-κB in biology and targeted therapy: new insights and translational implications

  2024cites this paper
• The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis

  2024cites this paper
• PUM1-TRAF3 fusion protein activates non-canonical NF-κB signaling via rescued NIK in biliary tract cancer

  2024cites this paper
• The noncanonical NFκB pathway: Regulatory mechanisms in health and disease.

  2024influential citation
• Advancements in B-Cell Non-Hodgkin's Lymphoma: From Signaling Pathways to Targeted Therapies

  2024cites this paper
• Dynamic modulation of the non-canonical NF-κB signaling pathway for HIV shock and kill

  2024cites this paper
• CRISPR-Cas9 screen of E3 ubiquitin ligases identifies TRAF2 and UHRF1 as regulators of HIV latency in primary human T cells

  2024cites this paper
• ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling

  2024cites this paper
• Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans

  2024cites this paper
• IL-1β stimulates a novel axis within the NFκB pathway in endothelial cells regulated by IKKα and TAK-1.

  2024cites this paper
• Functional RNAi Screening Identifies G2/M and Kinetochore Components as Modulators of TNFα/NF-κB Prosurvival Signaling in Head and Neck Squamous Cell Carcinoma

  2024cites this paper
• Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication

  2024cites this paper
• Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.

  2024cites this paper
• The molecular map of CLL and Richter's syndrome.

  2024cites this paper
• Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids

  2023cites this paper
• The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

  2023cites this paper
• The Roles of TRAF3 in Immune Responses

  2023cites this paper
• SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling

  2023cites this paper
• Filling a nick in NIK: extending the half-life of a NIK inhibitor through structure-based drug design.

  2023cites this paper
• Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases

  2023cites this paper
• NLRP12 Senses the SARS-CoV-2 Membrane Protein and Promotes an Inflammatory Response.

  2023cites this paper
• cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

  2023cites this paper
• The Role of Regulated Programmed Cell Death in Osteoarthritis: From Pathogenesis to Therapy

  2023cites this paper
• Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer

  2023cites this paper
• SMAC mimetics inhibit human T cell proliferation and fail to augment type 1 cytokine responses.

  2023cites this paper
• Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling

  2023cites this paper
• Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis

  2023cites this paper
• cIAPs control RIPK1 kinase activity‐dependent and ‐independent cell death and tissue inflammation

  2023cites this paper
• Aberrant accumulation of NIK promotes tumor growth by dysregulating translation and post-translational modifications in breast cancer

  2023influential citation
• E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies

  2023cites this paper
• Alternative Splicing of RIOK3 Engages the Noncanonical NFκB Pathway during Rift Valley Fever Virus Infection

  2023cites this paper
• The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity

  2023cites this paper
• Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2

  2023cites this paper
• TRAF3/STAT6 axis regulates macrophage polarization and tumor progression

  2023cites this paper
• Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells

  2023cites this paper
• Targeting up-regulated cIAP2 in SOX10-deficient drug tolerant melanoma.

  2023cites this paper
• IL-1β stimulates a novel, IKKα -dependent, NIK -independent activation of non-canonical NFκB signalling.

  2023cites this paper
• TRAF2/3 deficient B cells resist DNA damage-induced apoptosis via NF-κB2/XIAP/cIAP2 axis and IAP antagonist sensitizes mutant lymphomas to chemotherapeutic drugs

  2023cites this paper
• Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

  2023cites this paper
• Targeting Apoptosis in Cancer

  2022cites this paper
• The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

  2022cites this paper
• NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway

  2022cites this paper
• Characterization of TRAF2 in Nile tilapia: Expression profiles and the role in decreasing NF-κB pathway.

  2022cites this paper
• Identification of key proteins of cytopathic biotype bovine viral diarrhoea virus involved in activating NF-κB pathway in BVDV-induced inflammatory response

  2022cites this paper
• TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems

  2022cites this paper
• Loss-of-function mutations in melanocortin-1 receptor modulate immune response in teleost fishes.

  2022cites this paper
• Pathogenic signaling in multiple myeloma.

  2022cites this paper
• cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3

  2022cites this paper
• Cytoplasmic and Nuclear Functions of cIAP1

  2022cites this paper
• Analysis of RANK-c interaction partners identifies TRAF3 as a critical regulator of breast cancer aggressiveness

  2022cites this paper
• Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

  2022cites this paper
• Mechanisms underlying synergism between circularized tumor necrosis factor‐related apoptosis inducing ligand and bortezomib in bortezomib‐sensitive or ‐resistant myeloma cells

  2022cites this paper
• Co-Stimulatory Receptor Signaling in CAR-T Cells

  2022cites this paper
• TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer

  2022cites this paper
• Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy

  2022cites this paper
• Current strategies to induce selective killing of HIV‐1‐infected cells

  2022cites this paper
• NF-κB and its crosstalk with endoplasmic reticulum stress in atherosclerosis

  2022cites this paper
• NF-κB Inducing Kinase Regulates Intestinal Immunity and Homeostasis

  2022cites this paper
• SGK1 negatively regulates inflammatory immune responses and protects against alveolar bone loss through modulation of TRAF3 activity

  2022cites this paper
• Deubiquitinases in cell death and inflammation

  2022cites this paper
• Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice

  2022cites this paper
• Computational analysis of 4-1BB-induced NFκB signaling suggests improvements to CAR cell design

  2022cites this paper
• Advances in Immunosuppressive Agents Based on Signal Pathway

  2022cites this paper
• Extracellular fibrinogen-binding protein released by intracellular Staphylococcus aureus suppresses host immunity by targeting TRAF3

  2022cites this paper
• The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

  2022cites this paper
• Regulation of TNF-Induced Osteoclast Differentiation

  2021cites this paper
• NF‐κB signaling in inflammation and cancer

  2021cites this paper
• SMYD2‐mediated TRAF2 methylation promotes the NF‐κB signaling pathways in inflammatory diseases

  2021cites this paper
• Unleashing TNF cytotoxicity to enhance cancer immunotherapy.

  2021cites this paper
• Chaperone-assisted E3 ligase CHIP: A double agent in cancer

  2021cites this paper
• Mitochondrial Fission Factor Is a Novel Interacting Protein of the Critical B Cell Survival Regulator TRAF3 in B Lymphocytes

  2021cites this paper
• Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis

  2021cites this paper
• TIFA has dual functions in Helicobacter pylori‐induced classical and alternative NF‐κB pathways

  2021cites this paper
• Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations—NOTCH1, SF3B1, MYD88, BIRC3

  2021cites this paper
• Manganese-induced reactive oxygen species activate IκB kinase to upregulate YY1 and impair glutamate transporter EAAT2 function in human astrocytes in vitro.

  2021cites this paper
• Aberrant accumulation of NIK promotes tumorigenicity by dysregulating post-translational modifications in breast cancer

  2021cites this paper
• Inhibitory feedback control of NF-κB signalling in health and disease

  2021cites this paper
• Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

  2021cites this paper
• Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

  2021cites this paper
• DYRK1a mediates BAFF-induced noncanonical NF-kB activation to promote autoimmunity and B cell leukemogenesis.

  2021cites this paper
• An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase.

  2021cites this paper
• Immunoblot Analysis of the Regulation of TNF Receptor Family-Induced NF-κB Signaling by c-IAP Proteins.

  2021cites this paper
• Naa10p and IKKα interaction regulates EMT in oral squamous cell carcinoma via TGF‐β1/Smad pathway

  2021cites this paper