TIFA activates IκB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6

Kwee, Chee; Sun, Lijun; Inoue, Jun; Chen, Zhijian J.

doi:10.1073/pnas.0404132101

Cited by 120 publications

(119 citation statements)

References 27 publications

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“…Tubulin is used as a loading control. may facilitate TRAF6 stimulation of downstream pathways through oligomerization, similar to what has been shown for the TRAF6 interactor TIFA (45). In agreement with these results, we found that in the absence of NRIF, p75 was unable to activate the kinase (Fig.…”

Section: Discussionsupporting

confidence: 90%

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif؊/؊ sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif؊/؊ neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.The p75 neurotrophin receptor is a pleiotropic signaling molecule that regulates cellular survival, neurite outgrowth, and myelin formation (1). This founding member of the tumor necrosis factor receptor superfamily can directly bind all of the neurotrophins, including nerve growth factor (NGF), 1 brainderived neurotrophic factor (BDNF), and neurotrophin-3 and -4 (NT-3, NT-4), but it also functions as a co-receptor in a variety of protein complexes. p75 can interact with TrkA to form a high affinity neurotrophin binding site (2) and enhance survival signaling (3). It can also associate with the Nogo receptor and Lingo-1 and, upon interaction with myelin proteins, block neurite outgrowth (4, 5), and, together with Sortilin, the neurotensin 3 receptor, it binds the proform of NGF and initiates apoptosis (6). The divergent cellular responses depend on the receptor complex as well as the cellular context. For example, sympathetic neurons of superior cervical ganglia undergo a period of programmed cell death during ontogenesis, and NGF, supplied by the tissues innervated, prevents the loss of these neurons through binding to a p75-TrkA complex (7). In contrast, specific activation of p75 (8) or a p75-sortilin complex (6) induces apoptosis in the neurons. Genetic deletion of p75 prevents the normal period of cell death in the developing superior cervical ganglia (8, 9), thus demonstrating the key role of this receptor in regulating the survival of this neuronal population.How p75 initiates this variety of biological effects is not well understood; however, the stress kinase c-Jun N-terminal kinase, JNK, has been suggested to play a role in mediating this apoptotic signal. Neurotrophin activation of JNK through p75 correlates with the induction of cell death (43) and inhibition of the kinase prevents the receptor from killing (23, 10). Interestingly, c-Jun, the downstream target of the kinase, is not required for the receptor to activate apoptosis (11); however, other JNK substrates have been implicated in the p75 death ...

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Section: Discussionsupporting

confidence: 90%

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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“…79 Activation of IKK involves the TRAFinteracting protein with a forkhead-associated (FHA) domain (TIFA) protein. 80 TIFA promotes the oligomerization of TRAF6 and enhances the autoubiquitinating activity of TRAF6, thereby facilitating downstream activation of NF-kB and JNK. 80 Activation of the IKKs leads to downstream phosphorylation of members of the inhibitor of NF-kB (IkB) family, resulting in ubiquitin-directed proteasome-mediated degradation of the IkB members, thus permitting the release and nuclear translocation of the transcription factor, NF-kB.…”

Section: Myd88-dependent Signalingmentioning

confidence: 99%

“…80 TIFA promotes the oligomerization of TRAF6 and enhances the autoubiquitinating activity of TRAF6, thereby facilitating downstream activation of NF-kB and JNK. 80 Activation of the IKKs leads to downstream phosphorylation of members of the inhibitor of NF-kB (IkB) family, resulting in ubiquitin-directed proteasome-mediated degradation of the IkB members, thus permitting the release and nuclear translocation of the transcription factor, NF-kB. 81 In endothelial cells, degradation of the IkB protein is dependent on its tyrosine phosphorylation and is specific to the IkBa isoform, while IkBb and IkBg protein levels remain unchanged following LPS stimulation.…”

Section: Myd88-dependent Signalingmentioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

529

433

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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“…A role for oligomerization of TRAF6 in enhancing its ubiquitinating activity has also been postulated [39,42,43]. In fact, TRAF-interacting protein with a forkhead-associated domain (TIFA) was found to interact with TRAF6, thereby inducing TRAF6 oligomerization and enhancing TRAF6 ubiquitinating activity [50]. Endogenous TIFA constitutively associates with TRAF6, whereas it only interacts with IRAK-1 upon IL-1 stimulation [51].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

393

297

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Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

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TIFA activates IκB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6

Cited by 120 publications

References 27 publications

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Lipopolysaccharide signaling in endothelial cells

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

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