GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Medunjanin, Senad; Schleithoff, Lisa; Fiegehenn, Christian; Weinert, Sönke; Zuschratter, Werner; Braun‐Dullaeus, Ruediger C.

doi:10.1038/srep38553

Cited by 86 publications

(56 citation statements)

References 54 publications

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“…A study describing phosphorylation of Ser43 in NEMO by IKKβ lacks a functional explanation regarding the importance of Ser43 in NEMO for NF-kB activation [31]. Previously, we identified GSK-3β as a kinase that phosphorylates Ser8, 17, and 31 of NEMO during TNFα-induced NF-κB activation [23]. In this study, Ser43 was also found to be phosphorylated.…”

Section: Discussionsupporting

confidence: 46%

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DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

Medunjanin

Putzier

Nöthen

et al. 2020

Cell. Mol. Life Sci.

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The transcription factors of the nuclear factor κB (NF-κB) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-κB differs from the classical canonical pathway by shuttling of the NF-κB Essential Modifier (IKKγ/NEMO) subunit through the nucleus. Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). Blockade of DNA-PK by a specific shRNA or by DNA-PKcs-deficient cells abrogated NEMO entry into the nucleus, as well. Accordingly, SUMOylation of NEMO, a prerequisite of nuclear NEMO, was abolished. Based on these observations, we propose a model in which NEMO phosphorylation by DNA-PK provides the first step in the nucleocytoplasmic trafficking of NEMO.

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Section: Discussionsupporting

confidence: 46%

“…Fixation and staining of the cells for stimulated emission depletion (STED) microscopy have been described previously [23]. Incubation with the primary antibody was performed overnight at 4 °C.…”

Section: Staining Of Cell Cultures For Sted Microscopymentioning

confidence: 99%

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

Medunjanin

Putzier

Nöthen

et al. 2020

Cell. Mol. Life Sci.

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“…Moreover, binding and phosphorylation (especially at Ser8, 17, and 31) of NF-κB essential modifier (NEMO, aka IKKγ) by GSK3β is required for its stabilization and the proper mediation of NF-κB signaling. Artificial destabilization of NEMO by replacing the relevant GSK3 target residues by alanine is accompanied by increased Lys63-polyubiquitination of the remaining NEMO molecules, enhanced IKKα and β binding, and elevated constitutive IκBα degradation, effects that could be further intensified by GSK3 inhibition [240].…”

Section: Nf-κb-associated Signalingmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

102

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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“…The subsequent re-activation of the downstream mediator of IRS-1, Akt, has been shown to confer organ protection in many pre-clinical models associated with inflammation including sepsis (33)(34), hemorrhagic shock-induced organ dysfunction (35)(36), and diabetes (20) (37). Indeed re-activating GSK-3b is associated with increased conversion of glucose to glycogen, which could also be a factor contributing to the observed glucose lowering effects in vivo, and is a key regulator of NF-kB activation (38) (39). In the present study we demonstrate inhibition of BTK with ibrutinib protects against the development of insulin resistance by restoring insulin signalling, most likely due to reduced inflammation, in myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

Purvis

Collino

Tavio

et al. 2019

Preprint

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Activation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Bruton's tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3b pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-κB and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the proinflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1b and TNFa after LPS stimulation. In the present study we provide 'proof of concept' evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D. inhibition or genetic deletion of components of the NF-kB pathway i) prevent the development of high fat diet induced insulin resistance (20)(21) and ii) slows the progression of microvascular disease. It has a been demonstrated that myeloid specific deletion of IKK-b, but not deletion in hepatocytes or adipocytes that contributes to the development of insulin resistance (18). Currently there are no medicines available for diabetes that target inflammation and/or prevent the development of microvascular complications. Repurposing existing FDA approved medications that have potent anti-inflammatory effects for new indications could be a cost-effective approach to prevent and/or treat the development of microvascular complications of diabetes. Antiinflammatory agents have been shown to be powerful tools in pre-clinical models. However, to date little translational research as followed up on these successes.Bruton's tyrosine kinase (BTK) is a tyrosine kinase that plays an essential role in B lymphocyte development. Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia. As well as, being highly expressed in B-lymphocytes, BTK is also highly expressed in monocytes/macrophages (22), the latter is the key cell types that drives the development of insulin resistance. Importantly, BTK is not expressed in hepatocytes or adipocytes the main cell types effected by obesity induced insulin resistance (23). In monocyte/macrophages BTK has a proposed role in signal transduction downstream of numerous TLR's. XID mice, which have non-signaling kinase domain in BTK, have redu...

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GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Cited by 86 publications

References 54 publications

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

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