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NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity.

ABSTRACT: Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8⁺ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8⁺ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.

SUBMITTER: Gu M

PROVIDER: S-EPMC7855506 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hepatic NF-κB-Inducing Kinase and Inhibitor of NF-κB Kinase Subunit α Promote Liver Oxidative Stress, Ferroptosis, and Liver Injury.

Project description:Drug-induced hepatotoxicity limits development of new effective medications. Drugs and numerous endogenous/exogenous agents are metabolized/detoxified by hepatocytes, during which reactive oxygen species (ROS) are generated as a by-product. ROS has broad adverse effects on liver function and integrity, including damaging hepatocyte proteins, lipids, and DNA and promoting liver inflammation and fibrosis. ROS in concert with iron overload drives ferroptosis. Hepatic nuclear factor kappa B (NF-κB)-inducing kinase (NIK) is aberrantly activated in a broad spectrum of liver disease. NIK phosphorylates and activates inhibitor of NF-κB kinase subunit alpha (IKKα), and the hepatic NIK/IKKα cascade suppresses liver regeneration. However, the NIK/IKKα pathway has not been explored in drug-induced liver injury. Here, we identify hepatic NIK as a previously unrecognized mediator for acetaminophen (APAP)-induced acute liver failure. APAP treatment increased both NIK transcription and NIK protein stability in primary hepatocytes as well as in liver in mice. Hepatocyte-specific overexpression of NIK augmented APAP-induced liver oxidative stress in mice and increased hepatocyte death and mortality in a ROS-dependent manner. Conversely, hepatocyte-specific ablation of NIK or IKKα mitigated APAP-elicited hepatotoxicity and mortality. NIK increased lipid peroxidation and cell death in APAP-stimulated primary hepatocytes. Pretreatment with antioxidants or ferroptosis inhibitors blocked NIK/APAP-induced hepatocyte death. Conclusion: We unravel a previously unrecognized NIK/IKKα/ROS/ferroptosis axis engaged in liver disease progression.

| S-EPMC8485893 | biostudies-literature

Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice.

Project description:The conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.

| S-EPMC9758150 | biostudies-literature

The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB-Inducing Kinase.

Project description:NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.

| S-EPMC6999715 | biostudies-literature

Cell intrinsic role of NF-κB-inducing kinase in regulating T cell-mediated immune and autoimmune responses.

Project description:NF-κB inducing kinase (NIK) is a central component of the noncanonical NF-κB signaling pathway. Although NIK has been extensively studied for its function in the regulation of lymphoid organ development and B-cell maturation, the role of NIK in regulating T cell functions remains unclear and controversial. Using T cell-conditional NIK knockout mice, we here demonstrate that although NIK is dispensable for thymocyte development, it has a cell-intrinsic role in regulating the homeostasis and function of peripheral T cells. T cell-specific NIK ablation reduced the frequency of effector/memory-like T cells and impaired T cell responses to bacterial infection. The T cell-conditional NIK knockout mice were also defective in generation of inflammatory T cells and refractory to the induction of a T cell-dependent autoimmune disease, experimental autoimmune encephalomyelitis. Our data suggest a crucial role for NIK in mediating the generation of effector T cells and their recall responses to antigens. Together, these findings establish NIK as a cell-intrinsic mediator of T cell functions in both immune and autoimmune responses.

| S-EPMC4766435 | biostudies-other

Activation of NF-κB-Inducing Kinase in Islet β Cells Causes β Cell Failure and Diabetes.

Project description:Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H2O2-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes.

| S-EPMC7647925 | biostudies-literature

NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus.

Project description:NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.

| S-EPMC5766581 | biostudies-literature

An NF-κB/IRF1 axis programs cDC1 to drive antitumor immunity

Project description:Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti -tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.

2021-08-16 | GSE171870 | GEO

Immunologic reconstitution following hematopoietic stem cell transplantation despite lymph node paucity in NF-κB-inducing kinase deficiency.

Project description: Not available

| S-EPMC6408971 | biostudies-literature

NF-κB Activity Initiates Human ESC-Derived Neural Progenitor Cell Differentiation by Inducing a Metabolic Maturation Program.

Project description:Human neural development begins at embryonic day 19 and marks the beginning of organogenesis. Neural stem cells in the neural tube undergo profound functional, morphological, and metabolic changes during neural specification, coordinated by a combination of exogenous and endogenous cues. The temporal cell signaling activities that mediate this process, during development and in the postnatal brain, are incompletely understood. We have applied gene expression studies and transcription factor-activated reporter lentiviruses during in vitro neural specification of human pluripotent stem cells. We show that nuclear factor κB orchestrates a multi-faceted metabolic program necessary for the maturation of neural progenitor cells during neurogenesis.

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NF-κB inducing kinase, a central signaling component of the non-canonical pathway of NF-κB, contributes to ovarian cancer progression.

Project description:Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-κB (NF-κB) is constitutively activated in several types of cancer including ovarian cancer and is known to support the survival of cancer cells. However, molecular mechanisms of persistent activation of NF-κB in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-κB is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-κB inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-κB2/p52 DNA binding activity and NF-κB-dependent reporter gene expression as well as NF-κB target gene expression. Notably, anchorage-dependent and -independent cell growth was impaired in NIK-depleted cells. Depletion of NIK also suppressed tumor formation in the nude mouse xenograft assay. These results indicate that NIK plays a key role in constitutive NF-κB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.

| S-EPMC3922808 | biostudies-literature

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