The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

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Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis

Mediators of Inflammation ◽

10.1155/2019/2945083 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Xuening Wang ◽

Dan Cheng ◽

Guanglei Hu ◽

Lili Liang ◽

Fei Tan ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Receptor Expression ◽

Structural Basis ◽

Tnf Receptor ◽

Death Domain ◽

Independent Manner ◽

Normal Keratinocytes ◽

Apoptosis Protein ◽

Necrosis Factor

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK’s regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

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Activation of p42/p44 mitogen-activated protein kinases (MAPK) and p38 MAPK by tumor necrosis factor (TNF) is mediated through the death domain of the 55-kDa TNF receptor

FEBS Letters ◽

10.1016/s0014-5793(98)01567-1 ◽

1998 ◽

Vol 441 (2) ◽

pp. 275-280 ◽

Cited By ~ 38

Author(s):

Elke Boone ◽

Veronique Vandevoorde ◽

Gert De Wilde ◽

Guy Haegeman

Keyword(s):

Tumor Necrosis Factor ◽

Protein Kinases ◽

P38 Mapk ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Death Domain ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein ◽

Necrosis Factor

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Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2005.01.140 ◽

2005 ◽

Vol 329 (1) ◽

pp. 397-405 ◽

Cited By ~ 17

Author(s):

Susan-Beatrice Csehi ◽

Sabine Mathieu ◽

Ulrike Seifert ◽

Arne Lange ◽

Margit Zweyer ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Insulin Signaling ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Death Domain ◽

Necrosis Factor

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Interaction of an Adenovirus E3 14.7-Kilodalton Protein with a Novel Tumor Necrosis Factor Alpha-Inducible Cellular Protein Containing Leucine Zipper Domains

Molecular and Cellular Biology ◽

10.1128/mcb.18.3.1601 ◽

1998 ◽

Vol 18 (3) ◽

pp. 1601-1610 ◽

Cited By ~ 133

Author(s):

Yongan Li ◽

Jian Kang ◽

Marshall S. Horwitz

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Leucine Zipper ◽

Tnf Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Early region 3 (E3) of group C human adenoviruses (Ad) encodes several inhibitors of tumor necrosis factor alpha (TNF-α) cytolysis, including an E3 14.7-kDa protein (E3-14.7K) and a heterodimer containing two polypeptides of 10.4 and 14.5 kDa. To understand the mechanism by which the viral proteins inhibit TNF-α functions, the E3-14.7K protein was used to screen a HeLa cell cDNA library to search for interacting proteins in the yeast two-hybrid system. A novel protein containing multiple leucine zipper domains without any significant homology with any known protein was identified and has been named FIP-2 (for 14.7K-interacting protein). FIP-2 interacted with E3-14.7K both in vitro and in vivo. It colocalized with Ad E3-14.7K in the cytoplasm, especially near the nuclear membrane, and caused redistribution of the viral protein. FIP-2 by itself does not cause cell death; however, it can reverse the protective effect of E3-14.7K on cell killing induced by overexpression of the intracellular domain of the 55-kDa TNF receptor or by RIP, a death protein involved in the TNF-α and Fas apoptosis pathways. Deletion analysis indicates that the reversal effect of FIP-2 depends on its interaction with E3-14.7K. Three major mRNA forms of FIP-2 have been detected in multiple human tissues, and expression of the transcripts was induced by TNF-α treatment in a time-dependent manner in two different cell lines. FIP-2 has consensus sequences for several potential posttranslational modifications. These data suggest that FIP-2 is one of the cellular targets for Ad E3-14.7K and that its mechanism of affecting cell death involves the TNF receptor, RIP, or a downstream molecule affected by either of these two molecules.

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A potential mechanism of "cross-talk" between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other.

Journal of Experimental Medicine ◽

10.1084/jem.183.3.1271 ◽

1996 ◽

Vol 183 (3) ◽

pp. 1271-1275 ◽

Cited By ~ 88

Author(s):

E E Varfolomeev ◽

M P Boldin ◽

T M Goncharov ◽

D Wallach

Keyword(s):

Tumor Necrosis Factor ◽

Cross Talk ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Functional Expression ◽

Sequence Motif ◽

Tnf Receptor ◽

Death Domain ◽

Cytoplasmic Proteins ◽

Necrosis Factor

The p55 tumor necrosis factor (TNF) receptor and Fas/APO1 induce cell death via distinct regions in their intracellular domains. Three cytoplasmic proteins that bind to these receptor regions have been identified recently. One, MORT1 (also called FADD), binds to Fas/APO1 but not to p55-R; another, TRADD, binds to the p55 TNF receptor but not to Fas/APO1; and the third, RIP, binds weakly to both receptors. The regions within these proteins that are involved in binding to the receptors and the receptor regions to which they bind share a common sequence motif, that of the "death domain." This study shows that the death domain motifs in MORT1, TRADD, and RIP bind effectively to each other, a mode of binding that may allow "cross-talk" between the functional expression of the p55 TNF receptor and Fas/APO1.

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Faculty Opinions recommendation of The C-terminal tails of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas receptors have opposing functions in Fas-associated death domain (FADD) recruitment and can regulate agonist-specific mechanisms of receptor activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1023152.264838 ◽

2005 ◽

Author(s):

Robert Kelley

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Receptor Activation ◽

Death Domain ◽

Necrosis Factor

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Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

Cell Death and Disease ◽

10.1038/s41419-021-03633-8 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Kirstin Kucka ◽

Isabell Lang ◽

Tengyu Zhang ◽

Daniela Siegmund ◽

Juliane Medler ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Asymmetric Structure ◽

Tnf Receptor ◽

Membrane Bound ◽

Necrosis Factor

AbstractIn the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2–LTβR system has been intensively studied while the LTα2β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.

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Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Protein Inhibits Tumor Necrosis Factor Alpha-Induced NF-κB Activation by Interacting with p65/RelA and p50/NF-κB1

Journal of Virology ◽

10.1128/jvi.01952-13 ◽

2013 ◽

Vol 87 (23) ◽

pp. 12935-12948 ◽

Cited By ~ 56

Author(s):

Jie Zhang ◽

Kezhen Wang ◽

Shuai Wang ◽

Chunfu Zheng

Keyword(s):

Tumor Necrosis Factor ◽

Ubiquitin Ligase ◽

Tumor Necrosis ◽

Nuclear Translocation ◽

E3 Ubiquitin Ligase ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor ◽

Hsv 1

NF-κB plays central roles in regulation of diverse biological processes, including innate and adaptive immunity and inflammation. HSV-1 is the archetypal member of the alphaherpesviruses, with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 ICP0 protein, a viral E3 ubiquitin ligase, was shown to significantly suppress tumor necrosis factor alpha (TNF-α)-mediated NF-κB activation. ICP0 was demonstrated to bind to the NF-κB subunits p65 and p50 by coimmunoprecipitation analysis. ICP0 bound to the Rel homology domain (RHD) of p65. Fluorescence microscopy demonstrated that ICP0 abolished nuclear translocation of p65 upon TNF-α stimulation. Also, ICP0 degraded p50 via its E3 ubiquitin ligase activity. The RING finger (RF) domain mutant ICP0 (ICP0-RF) lost its ability to inhibit TNF-α-mediated NF-κB activation and p65 nuclear translocation and degrade p50. Notably, the RF domain of ICP0 was sufficient to interact with p50 and abolish NF-κB reporter gene activity. Here, it is for the first time shown that HSV-1 ICP0 interacts with p65 and p50, degrades p50 through the ubiquitin-proteasome pathway, and prevents NF-κB-dependent gene expression, which may contribute to immune evasion and pathogenesis of HSV-1.

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