scholarly journals A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)

2003 ◽  
Vol 370 (1) ◽  
pp. 159-166 ◽  
Author(s):  
Ken YANAGISAWA ◽  
Kenji TAGO ◽  
Morisada HAYAKAWA ◽  
Motomichi OHKI ◽  
Hiroyuki IWAHANA ◽  
...  
Keyword(s):  
Splice Variant ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Acceptor Site ◽  
Nuclear Factor ◽  
Death Domain ◽  
Signalling Molecule ◽  
Novel Variant ◽  
Nf Kappab

Interleukin-1 (IL-1)-receptor-associated kinase (IRAK) is an indispensable signalling molecule for host-defence responses initiated by a variety of ligands that bind to members of the Toll/IL-1 receptor family. Here we report a novel splice variant of mouse IRAK-1, IRAK-1-S, which is generated by utilizing a new splicing acceptor site within exon 12. IRAK-1-S cDNA is shorter than the originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent frameshift causes a premature termination of translation after 23 amino acids, which are unique to the IRAK-1-S protein. To elucidate the physiological function of IRAK-1-S, we overexpressed it in 293T cells and studied the effects on the IL-1 signalling cascade. As it lacks the C-terminal region of IRAK-1-W that has been reported to contain the TRAF6 (tumour necrosis factor receptor-associated factor 6) binding domain, IRAK-1-S was unable to bind TRAF6 protein, which is a proposed downstream signalling molecule. However, IRAK-1-S overexpressed in 293T cells induced constitutive activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) independent of stimulation by IL-1, as did IRAK-1-W. To clarify the mechanism of NF-κB activation by IRAK-1-S in the absence of binding to TRAF6, we demonstrated that IRAK-1-S binds to IRAK-1-W through its death domain; the findings suggested that overexpressed IRAK-1-S may bind endogenous IRAK-1-W and activate TRAF6 through IRAK-1-W. These results also indicate that this novel variant may play roles in the activation of NF-κB and JNK by IL-1 and other ligands whose signal transduction is dependent on IRAK-1 under physiological conditions.

scholarly journals Interleukin-1-receptor-associated kinase 2 (IRAK2)-mediated interleukin-1-dependent nuclear factor κB transactivation in Saos2 cells requires the Akt/protein kinase B kinase

2003 ◽  
Vol 376 (1) ◽  
pp. 303-311 ◽  
Author(s):  
Vittoria CENNI ◽  
Alessandra SIRRI ◽  
Anto De Pol ◽  
Nadir Mario MARALDI ◽  
Sandra MARMIROLI
Keyword(s):  
Protein Kinase ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Tumour Necrosis Factor Receptor ◽  
Nuclear Factor ◽  
Transactivation Domain ◽  
Defective Mutant ◽  
Gene Reporter Assay ◽  
Pre Treatment

The post-receptor pathway that leads to nuclear factor κB (NF-κB) activation begins with the assembly of a membrane-proximal complex among the interleukin 1 (IL-1) receptors and the adaptor molecules, myeloid differentiation protein 88 (MyD88), IL-1-receptor-associated kinases (IRAKs) and tumour-necrosis-factor-receptor-associated factor 6. Eventually, phosphorylation of the inhibitor of NF-κB (IκB) by the IκB kinases releases NF-κB, which translocates to the nucleus and modulates gene expression. In this paper, we report that IRAK2 and MyD88, but not IRAK1, interact physically with Akt, as demonstrated by co-immunoprecipitation and pull-down experiments. Interestingly, the association of Akt with recombinant IRAK2 is decreased by stimulation with IL-1, and is favoured by pre-treatment with phosphatase. Likewise, Akt association with IRAK2 is increased considerably by overexpression of PTEN (phosphatase and tensin homologue deleted on chromosome 10), while it is completely abrogated by overexpression of phosphoinositide-dependent protein kinase 1. These data indicate that Akt takes part in the formation of the signalling complex that conveys the signal from the IL-1 receptors to NF-κB, a step that is much more membrane-proximal than was reported previously. We also demonstrate that Akt activity is necessary for IL-1-dependent NF-κB transactivation, since a kinase-defective mutant of Akt impairs IRAK2- and MyD88-dependent, but not IRAK1-dependent, NF-κB activity, as monitored by a gene reporter assay. Accordingly, IRAK2 failed to trigger inducible nitric oxide synthase and IL-1β production in cells expressing dominant-negative Akt. However, NF-κB binding to DNA was not affected by inhibition of Akt, indicating that Akt regulates NF-κB at a level distinct from the dissociation of p65 from IκBα and its translocation to the nucleus, possibly involving phosphorylation of the p65 transactivation domain.

scholarly journals The role of TBK1 and IKKϵ in the expression and activation of Pellino 1

2011 ◽  
Vol 434 (3) ◽  
pp. 537-548 ◽  
Author(s):  
Hilary Smith ◽  
Xin-Yu Liu ◽  
Liang Dai ◽  
Eddy T. H. Goh ◽  
Aye-Thu Chan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Interleukin 1 ◽  
E3 Ligase ◽  
Nuclear Factor Κb ◽  
Poly I:C ◽  
Tumour Necrosis Factor Receptor ◽  
Nuclear Factor ◽  
Gene Encoding ◽  
Gene And Protein Expression

Mammalian Pellino isoforms are phosphorylated by IRAK (interleukin receptor associated kinase) 1/IRAK4 in vitro, converting them into active E3 ubiquitin ligases. In the present paper we report a striking enhancement in both transcription of the gene encoding Pellino 1 and Pellino 1 protein expression when murine BMDMs (bone-marrow-derived macrophages) are stimulated with LPS (lipopolysaccharide) or poly(I:C). This induction occurs via a TRIF [TIR (Toll/interleukin-1 receptor)-domain-containing adaptor-inducing interferon-β]-dependent IRAK-independent pathway and is prevented by inhibition of the IKK [IκB (inhibitor of nuclear factor κB) kinase]-related protein kinases, TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1} and IKKϵ. Pellino 1 is not induced in IRF3 (interferon regulatory factor 3)−/− BMDMs, and its induction is only reduced slightly in type 1 interferon receptor−/− BMDMs, identifying Pellino 1 as a new IRF3-dependent gene. We also identify Pellino 1 in a two-hybrid screen using IKKϵ as bait, and show that IKKϵ/TBK1 activate Pellino 1 in vitro by phosphorylating Ser76, Thr288 and Ser293. Moreover, we show that the E3 ligase activity of endogenous Pellino 1 is activated in LPS- or poly(I:C)-stimulated macrophages. This occurs more rapidly than the increase in Pellino 1 mRNA and protein expression, is prevented by the inhibition of IKKϵ/TBK1 and is reversed by phosphatase treatment. Thus IKKϵ/TBK1 mediate the activation of Pellino 1's E3 ligase activity, as well as inducing the transcription of its gene and protein expression in response to TLR3 and TLR4 agonists.

Is the Effect of Interleukin-1 on Glutathione Oxidation in Cultured Human Fibroblasts Involved in Nuclear Factor-κB Activation?

2001 ◽  
Vol 3 (2) ◽  
pp. 329-340 ◽  
Author(s):  
Patricia Renard ◽  
Edouard Delaive ◽  
Martine Van Steenbrugge ◽  
José Remacle ◽  
Martine Raes
Keyword(s):  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cultured Human Fibroblasts ◽  
Glutathione Oxidation

scholarly journals Predictive Value of Nuclear Factor κB Activity and Plasma Cytokine Levels in Patients with Sepsis

2000 ◽  
Vol 68 (4) ◽  
pp. 1942-1945 ◽  
Author(s):  
Francisco Arnalich ◽  
Esther Garcia-Palomero ◽  
Julia López ◽  
Manuel Jiménez ◽  
Rosario Madero ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Regulatory Protein ◽  
Nuclear Factor Κb ◽  
Apache Ii Score ◽  
Nuclear Factor ◽  
Early Measurement ◽  
Peripheral Blood Mononuclear ◽  
Cytokine Levels

ABSTRACT The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex. We postulated that early measurement of the activation of nuclear factor κB (NF-κB), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis. We determined NF-κB activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma. NF-κB activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels. Apart from NF-κB activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis. These results underscore the prognostic value of early measurement of NF-κB activity in patients with severe sepsis.

6-Gingerol Ameliorates Sepsis Induced Acute Lung Injury by Regulating Nuclear Factor-κB and Nuclear-Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Signaling Pathways

2020 ◽  
Vol 19 (3) ◽  
pp. 255-260
Author(s):  
Fan Yang ◽  
Lu Deng ◽  
MuHu Chen ◽  
Ying Liu ◽  
Jianpeng Zheng
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Alveolar Collapse ◽  
Factor Α

Acute lung injury initiated systemic inflammation leads to sepsis. Septic mice show a series of degenerative changes in lungs as demonstrated by pulmonary congestion, alveolar collapse, inflammatory cell infiltration, and increased wet-todry weight in lungs. 6-Gingerol ameliorates histopathological changes and clinical outcome of the sepsis. The increase in the levels of tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interleukin-18 in septic mice were reduced by administration with 6-Gingerol. Also, 6-Gingerol attenuates sepsis-induced increase of malonaldehyde and decrease of catalase, superoxide, and glutathione. Enhanced phospho-p65, reduced nuclear factor erythropoietin-2-related factor 2, and heme oxygenase 1 in septic mice were reversed by administration with 6-Gingerol. In conclusion, 6-Gingerol demonstrates anti-inflammatory and antioxidant effects against sepsis associated acute lung injury through inactivation of nuclear factor-kappa B and activation of nuclear-factor erythroid 2-related factor 2 pathways.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

scholarly journals UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation

2011 ◽  
Vol 22 (8) ◽  
pp. 1389-1397 ◽  
Author(s):  
Yuefeng Huang ◽  
Liang Chen ◽  
Yi Zhou ◽  
Heng Liu ◽  
Jueqing Yang ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Receptor Complex ◽  
Tnf Receptor ◽  
Death Domain ◽  
Complex Ii ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Necrosis Factor

Proteins that directly regulate tumor necrosis factor (TNF) signaling have critical roles in determining cell death and survival. Previously we characterized ubiquitously expressed transcript (UXT)-V2 as a novel transcriptional cofactor to regulate nuclear factor-κB in the nucleus. Here we report that another splicing isoform of UXT, UXT-V1, localizes in cytoplasm and regulates TNF-induced apoptosis. UXT-V1 knockdown cells are hypersensitive to TNF-induced apoptosis. We demonstrated that UXT-V1 is a new component of TNF receptor signaling complex. We found that UXT-V1 binds to TNF receptor-associated factor 2 and prevents TNF receptor–associated death domain protein from recruiting Fas-associated protein with death domain. More importantly, UXT-V1 is a short-half-life protein, the degradation of which facilitates the formation of the apoptotic receptor complex II in response to TNF treatment. This study demonstrates that UXT-V1 is a novel regulator of TNF-induced apoptosis and sheds new light on the underlying molecular mechanism of this process.

Sign in / Sign up

Export Citation Format

Share Document