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Limited activation interdependence, and differing patterns of the in vivo effects, of IKK1 and IKK2 downstream of NIK

ABSTRACT: The protein kinase NIK controls numerous immune functions by signaling for the processing of NF-kB2 and for the activation of other NF-kB proteins. NIK associates with IKK1 and has been suggested to exert all its effects via IKK1 activation. In this study, we demonstrate that NIK, by binding to IKK1, also associates with IKK2 and NEMO, allowing NIK to dictate the phosphorylation of IKK2 independently of IKK1's enzymatic function. IKK2 activation is also maintained when the phosphorylation of NF-κB2 is compromised by a mutation of NIK that affects its interaction with IKK1 and NF-kB2. Analyzing mice with this mutation reveals the differing dependencies of various effects of NIK on the activation of IKK1 or IKK2 and on the activation of differing NF-kB proteins. These findings indicate that NIK’s signaling mechanisms for the activation of different NF-kB proteins by the two IKKs are not strictly coupled.

ORGANISM(S): Mus musculus

PROVIDER: GSE306633 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Limited activation interdependence, and differing patterns of the in vivo effects, of IKK1 and IKK2 downstream of NIK

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