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Cell Research Jan 2011The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on... (Review)
Review
The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.
Topics: Endonucleases; Humans; I-kappa B Kinase; NF-kappa B; Nuclear Proteins; Protein Serine-Threonine Kinases; Signal Transduction; NF-kappaB-Inducing Kinase
PubMed: 21173796
DOI: 10.1038/cr.2010.177 -
Biochemical Pharmacology Jun 2022The interferon regulatory factor (IRF) family of transcription factors play a vital role in the human innate antiviral immune responses with production of interferons... (Review)
Review
The interferon regulatory factor (IRF) family of transcription factors play a vital role in the human innate antiviral immune responses with production of interferons (IFNs) as a hallmark outcome of activation. In recent years, IRF3 has been considered a principal early regulator of type I IFNs (TI-IFNs) directly downstream of intracellular virus sensing. Despite decades of research on IRF-activating pathways, many questions remain on the regulation of IRF3 activation. The kinases IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1) and the scaffold proteins TRAF family member-associated NF-kappa-B activator (TANK), NF-kappa-B-activating kinase-associated protein 1 (NAP1) and TANK-binding kinase 1-binding protein 1 (TBKBP1)/similar to NAP1 TBK1 adaptor (SINTBAD) are believed to be core components of an IRF3-activation complex yet their contextual involvement and complex composition are still unclear. This review will give an overview of antiviral signaling pathways leading to the activation of IRF3 and discuss recent developments in our understanding of its proximal regulation.
Topics: Humans; I-kappa B Kinase; Immunity, Innate; Interferon Regulatory Factor-3; Phosphorylation; Signal Transduction; Virus Diseases
PubMed: 35367198
DOI: 10.1016/j.bcp.2022.115026 -
Molecular Cell Jul 2022The NF-κB essential modulator (NEMO) is a regulatory subunit of the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors IκBs. NEMO mediates IKK...
The NF-κB essential modulator (NEMO) is a regulatory subunit of the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors IκBs. NEMO mediates IKK activation by binding to polyubiquitin chains (polyUb). Here, we show that Lys63(K63)-linked or linear polyUb binding to NEMO robustly induced the formation of liquid-like droplets in which IKK was activated. This liquid phase separation of NEMO was driven by multivalent interactions between NEMO and polyUb. Both the NEMO ubiquitin-binding (NUB) domain and the zinc-finger (ZF) domain of NEMO mediated binding to polyUb and contributed to NEMO phase separation and IKK activation in cells. Moreover, NEMO mutations associated with human immunodeficiency impaired its phase separation. These results demonstrate that polyUb activates IKK and NF-κB signaling by promoting the phase separation of NEMO.
Topics: Humans; I-kappa B Kinase; NF-kappa B; Polyubiquitin; Signal Transduction; Ubiquitin
PubMed: 35477005
DOI: 10.1016/j.molcel.2022.03.037 -
Cell Reports Apr 2020Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once...
Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity.
Topics: Animals; Female; HEK293 Cells; Humans; I-kappa B Kinase; Immunity, Innate; Interferon Regulatory Factor-3; Interferon-beta; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myeloid Cells; NF-kappa B; Nucleotides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 32268090
DOI: 10.1016/j.celrep.2020.03.056 -
Science Advances Jan 2021Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here,...
Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.
Topics: Animals; Annexin A1; Autophagy; Brain Ischemia; I-kappa B Kinase; Mice; Microglia; Sumoylation
PubMed: 33523920
DOI: 10.1126/sciadv.abc5539 -
Immunological Reviews Mar 2012The inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex is the master regulator of the NF-κB signaling pathway. The activation of the IKK complex is a tightly... (Review)
Review
The inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex is the master regulator of the NF-κB signaling pathway. The activation of the IKK complex is a tightly regulated, highly stimulus-specific, and target-specific event that is essential for the plethora of functions attributed to NF-κB. More recently, NF-κB-independent roles of IKK members have brought increased complexity to its biological function. This review highlights some of the major advances in the studies of the process of IKK activation and the biological roles of IKK family members, with a focus on NF-κB-independent functions. Understanding these complex processes is essential for targeting IKK for therapeutics.
Topics: Animals; Enzyme Activation; Humans; I-kappa B Kinase; Protein Kinase Inhibitors; Signal Transduction
PubMed: 22435559
DOI: 10.1111/j.1600-065X.2012.01107.x -
Journal of Interferon & Cytokine... Apr 2012IκB kinase alpha (Ikk-α) gene mutations and IKK-α downregulation have been detected in various human squamous cell carcinomas (SCCs), which are malignancies derived... (Review)
Review
IκB kinase alpha (Ikk-α) gene mutations and IKK-α downregulation have been detected in various human squamous cell carcinomas (SCCs), which are malignancies derived from squamous epithelial cells. These squamous epithelial cells distribute to many organs in the body; however, the epidermis is the only organ mainly composed of stratified squamous epithelial cells, called keratinocytes. SCC is the second most common type of skin cancer. Reducing IKK-α expression promotes tumor initiation, and its loss greatly enhances tumor progression from benign papillomas to malignant carcinomas during chemical skin carcinogenesis in mice. Thus, IKK-α has emerged as a tumor suppressor for SCCs. Furthermore, inducible deletion of IKK-α in the keratinocytes of adult mice causes spontaneous skin papillomas and carcinomas, indicating that IKK-α deletion functions as a tumor initiator as well as a tumor promoter. This article discusses IKK-α biological activities and associated molecular events in skin tumor development, which may provide insight into the diagnosis, treatment, and prevention of human squamous cell carcinomas (SCCs) in the future.
Topics: Animals; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Humans; I-kappa B Kinase; Inflammation; Models, Biological; Signal Transduction; Skin Neoplasms
PubMed: 22149351
DOI: 10.1089/jir.2011.0107 -
EMBO Reports Jan 2014The IκB kinase (IKK) complex is the signal integration hub for NF-κB activation. Composed of two serine-threonine kinases (IKKα and IKKβ) and the regulatory subunit... (Review)
Review
The IκB kinase (IKK) complex is the signal integration hub for NF-κB activation. Composed of two serine-threonine kinases (IKKα and IKKβ) and the regulatory subunit NEMO (also known as IKKγ), the IKK complex integrates signals from all NF-κB activating stimuli to catalyze the phosphorylation of various IκB and NF-κB proteins, as well as of other substrates. Since the discovery of the IKK complex components about 15 years ago, tremendous progress has been made in the understanding of the IKK architecture and its integration into signaling networks. In addition to the control of NF-κB, IKK subunits mediate the crosstalk with other pathways, thereby extending the complexity of their biological function. This review summarizes recent advances in IKK biology and focuses on emerging aspects of IKK structure, regulation and function.
Topics: Animals; Feedback, Physiological; Humans; I-kappa B Kinase; NF-kappa B; Phosphorylation; Protein Interaction Maps; Protein Multimerization; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 24375677
DOI: 10.1002/embr.201337983 -
The Journal of Cell Biology Feb 2024Cytoplasmic aggregation of TDP-43 in neurons is a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We...
Cytoplasmic aggregation of TDP-43 in neurons is a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We demonstrate that the IκB kinase (IKK) complex promotes the degradation of cytoplasmic TDP-43 through proteasomes. While IKKβ is a major factor in TDP-43 degradation, IKKα acts as a cofactor, and NEMO functions as a scaffold for the recruitment of TDP-43 to the IKK complex. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. TDP-43 phosphorylation at Ser92 was detected in a pattern different from that of C-terminal phosphorylation in the pathological inclusion of ALS. IKKβ was also found to significantly reduce the expression level and toxicity of the disease-causing TDP-43 mutation. Finally, the favorable effect of IKKβ on TDP-43 aggregation was confirmed in the hippocampus of mice. IKK and the N-terminal phosphorylation of TDP-43 are potential therapeutic targets for ALS and FTLD.
Topics: Animals; Mice; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; I-kappa B Kinase; Proteasome Endopeptidase Complex; Disease Models, Animal
PubMed: 38197897
DOI: 10.1083/jcb.202302048 -
Virologica Sinica Dec 2016IκB kinase ε (IKKε) is a non-canonical IκB kinase that is extensively studied in the context of innate immune response. Recently, significant progress has been made... (Review)
Review
IκB kinase ε (IKKε) is a non-canonical IκB kinase that is extensively studied in the context of innate immune response. Recently, significant progress has been made in understanding the role of IKKε in interferon (IFN) signaling. In addition to its roles in innate immunity, recent studies also demonstrate that IKKε is a key regulator of the adaptive immune response. Specifically, IKKε functions as a negative feedback kinase to curtail CD8 T cell response, implying that it can be a potential therapeutic target to boost antiviral and antitumor T cell immunity. In this review, we highlight the roles of IKKε in regulating IFN signaling and T cell immunity, and discuss a few imminent questions that remain to be answered.
Topics: Animals; Humans; I-kappa B Kinase; Immunity, Innate; Interferons; Neoplasms; Signal Transduction; T-Lymphocytes; Virus Diseases
PubMed: 28063014
DOI: 10.1007/s12250-016-3898-y