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Last update 08 May 2025

NFKBIZ

Last update 08 May 2025

Basic Info

Synonyms

FLJ34463, I-kappa-B-zeta, IkappaBzeta

+ [11]

Introduction

Involved in regulation of NF-kappa-B transcription factor complexes (PubMed:16513645, PubMed:16622025). Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation (PubMed:16513645). Inhibits DNA-binding of RELA and NFKB1/p50, and of the NF-kappa-B p65-p50 heterodimer and the NF-kappa-B p50-p50 homodimer (PubMed:16513645). Seems also to activate NF-kappa-B-mediated transcription (PubMed:16622025). In vitro, upon association with NFKB1/p50 has transcriptional activation activity and, together with NFKB1/p50 and RELA, is recruited to LCN2 promoters (PubMed:16622025). Promotes transcription of LCN2 and DEFB4 (PubMed:16622025). Is recruited to IL-6 promoters and activates IL-6 but decreases TNF-alpha production in response to LPS (By similarity). Seems to be involved in the induction of inflammatory genes activated through TLR/IL-1 receptor signaling (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR) (By similarity).

Drugs associated with NFKBIZ

CN118667767

Patent Mining

Target

NFKBIZ

Mechanism

NFKBIZ inhibitors

Active Org.

Shanghai Jiao Tong University

Originator Org.

Shanghai Jiao Tong University

Active Indication

Inflammation [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NFKBIZ

100 Translational Medicine associated with NFKBIZ

0 Patents (Medical) associated with NFKBIZ

309

Literatures (Medical) associated with NFKBIZ

04 May 2025·Autophagy

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival

Article

Author: Winklhofer, Konstanze F. ; Mari, Muriel C. ; Balta, Denise ; Scheuer, Christoph ; Behrends, Christian ; Zellner, Suzanne ; Vandrey, Julia ; Zein, Laura ; Zunke, Friederike ; Van Wijk, Sjoerd J. L. ; Dietrich, Marvin ; Bader, Verian ; Weinelt, Nadine

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A₁; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.

01 Mar 2025·Journal of Orthopaedic Science

Conditional deletion of IκBζ in hematopoietic cells promotes functional recovery after spinal cord injury in mice

Article

Author: Takeshita, Katsushi ; Maruyama, Takashi ; Ohmori, Tsukasa ; Kimura, Atsushi ; Shiraishi, Yasuyuki ; Taki, Naoya

BACKGROUNDTranscription factor protein IκBζ (encoded by the Nfkbiz gene) regulates nuclear factor-κB (NF-κB) and is involved in the pathophysiology of various inflammatory diseases. However, the role of IκBζ in secondary damage following spinal cord injury (SCI) remains to be determined. Here, we investigated the effect of IκBζ expressed in hematopoietic cells on the progression of secondary damage and functional recovery after SCI.METHODSWe used conditional IκBζ-knockout mice (Mx1-Cre;Nfkbiz^fl/f) to examine the role of IκBζ in hematopoietic cells after SCI. Contusion SCI was induced using a force of 60 kdyn. The recovery of locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS) until 42 days post-injury. Expression patterns of inflammatory cytokines and chemokines were examined by quantitative real-time PCR or proteome array analysis. Bone marrow transplantation (BMT) was performed to eliminate the effect of IκBζ deletion in non-hematopoietic cells.RESULTSMx1-Cre;Nfkbiz^fl/fl mice had significantly improved locomotor function compared with wild-type (WT) mice. The mRNA expression of Nfkbiz in WT mice peaked at 12 h after SCI and then decreased slowly in both the spinal cord and white blood cells. In situ hybridization showed that Nfkbiz mRNA was localized in cell nuclei, including macrophage-like cells, in the injured spinal cord of WT mice at 1 day after SCI. Compared with WT mice, Mx1-Cre;Nfkbiz^fl/fl mice had significantly increased mRNA expressions of interleukin (Il)-4 and Il-10 in the injured spinal cord. In addition, Mx1-Cre;Nfkbiz^fl/fl mice had significantly higher protein levels of granulocyte-macrophage colony-stimulating factor and C-C motif chemokine 11 compared with WT mice. BMT from Mx1-Cre;Nfkbiz^fl/fl mice into WT mice improved functional recovery after SCI compared with control mice (WT cells into WT mice).CONCLUSIONSIκBζ deletion in hematopoietic cells improved functional recovery after SCI, possibly by shifting the inflammatory balance towards anti-inflammatory and pro-regenerative directions.

01 Feb 2025·Arthritis & Rheumatology

IĸBζ as a Central Modulator of Inflammatory Arthritis Pathogenesis

Article

Author: Peterson, Timothy ; Gupta, Prashant ; Mims, Dorothy ; Singamaneni, Srikanth ; Swarnkar, Gaurav ; Abu‐Amer, Yousef ; Christopher, Matthew J. ; Naaz, Musarrat ; Mbalaviele, Gabriel

ObjectiveCurrent therapies targeting individual factors in inflammatory arthritis show variable efficacy, often requiring treatment with combinations of drugs, and are associated with undesirable side effects. NF‐ĸB is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF‐ĸB is precarious. Hence, identifying pathways downstream of NF‐ĸB that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified IĸBζ as a unique inflammatory signature of NF‐ĸB that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF‐ĸB signals.MethodsWe generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding IĸBζ). These models were subjected to serum transfer‐induced arthritis. Additionally, pharmacologic inhibitors of IĸBζ were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples.ResultsGlobal deletion of Nfkbiz or depletion of neutrophils (vastly IĸBζ+ cells) reduced inflammatory synovial cells and increased anti‐inflammatory and regenerative synovial cells, plummeted expression of inflammatory factors and ameliorated experimental mouse inflammatory arthritis. Further, expression of immune responsive gene‐1, the enzyme responsible for itaconate production, was increased in synovial cells. Accordingly, the itaconate derivative dimethyl itaconate (DI) inhibited IĸBζ‐mediated inflammatory factors. Further, in silico screen identified 8‐hydroxyquinoline (HQ) as a putative inhibitor of IĸBζ not affecting physiologic NF‐ĸB activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage.ConclusionOur study positions IĸBζ as an inflammation‐specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF‐ĸB.

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