TRAF2 multitasking in TNF receptor-induced signaling to NF-κB, MAP kinases and cell death

Borghi, Alice; Verstrepen, Lynn; Beyaert, Rudi

doi:10.1016/j.bcp.2016.03.009

Cited by 179 publications

(141 citation statements)

References 86 publications

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“…Stimulation of the tumor necrosis factor receptor (TNFR) with the proinflammatory cytokine results in NF-κB activation, which is mediated by members of the TNFR-associated factor (TRAF) family characterized by a highly conserved TRAF domain and a RING domain. TRAF2, the most widely studied TRAF member, serves as a scaffold protein and E3 ubiquitin ligase by binding to numerous TNFR-family proteins to mediate the activation of the inhibitor of κB (IκB) kinase (IKK) and NF-κB (Borghi et al, 2016; Bradley and Pober, 2001). Previous studies have revealed extensive interaction between Nur77 and NF-κB signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

et al. 2017

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SUMMARY Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.

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Section: Introductionmentioning

confidence: 99%

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

et al. 2017

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“…In addition, TRAF2 can also bind to TNFR1 or TNFR2, which recruits TRAF2 when stimulated by TNF-α, thereby inducing downstream signals [42]. However, although the two receptors both combined with TRAF2, TNFR1- and TNFR2-induced signals are usually divergent in cell fate [46]. …”

Section: Structural Basis For the Interaction Between Fn14 Traf2 CImentioning

confidence: 99%

“…If the degradation of TRAF2 is blocked, the TNFR2 activation of the noncanonical NF-κB pathway may be eliminated, possibly leading to T-cell dysregulation. Inducing, instead of blocking, TRAF2 degradation is favorable for cell apoptosis and in some cases can be beneficial as an anticancer strategy [46]. Multimerization of anti-Fn14 antibodies mediated by an Fc receptor may promote the efficiency of their agonistic activity, leading to a more efficient induction of cell death [55].…”

Section: Application Of the Fn14-traf2-tnfr Axis In Therapeutic Stratmentioning

confidence: 99%

“…The RING finger protein TRAF2 plays a key role in TNFR1- and TNFR2-induced signaling. TRAF2 can be recruited to TNFR1 or TNFR2 and even mediates the cross talk between TNFR1 and TNFR2 [46]. TNFR2 activation also induces the degradation of TRAF2 [45].…”

Section: Switch In Cell Phenotype Reverses the Direction Of Tweak Regmentioning

confidence: 99%

“…The TNFR1 signaling pathway is activated by the signals of apoptosis or necroptosis, which are contingent on the environments and cellular states [46]. TNFR1 signaling either induces the synthesis of multiple inflammatory mediators and growth factors through NF-κB activation or can result in the induction of cell death through its death domain through the TNF receptor–associated protein with death domain or the Fas-associated protein with death domain, which mediates cell death signaling [42, 47].…”

Section: Switch In Cell Phenotype Reverses the Direction Of Tweak Regmentioning

confidence: 99%

See 2 more Smart Citations

Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling

Wang¹,

Xiao²,

Xia³

2017

Cell Physiol Biochem

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Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) engages its sole receptor, fibroblast growth factor–inducible 14 (Fn14), which participates in various inflammatory and immunologic processes. TWEAK/Fn14 interaction induces different cell fates depending on the local microenvironment, which correlates with certain expression profiles of TNF receptors (TNFR). The predominant expression of TNFR1 or TNFR2 facilitates cell death or proliferation, respectively, on TWEAK/Fn14 activation. TNFR-associated factors (TRAF) interact with Fn14, cellular inhibitor of apoptosis protein (cIAP)-1, and TNFR, consequently transducing signals from TWEAK to downstream cytokines and cell cycle mediators. An Fn14-TRAF2-TNFR axis has been suggested in the function of TWEAK/Fn14 signaling, which may serve as a target in the development of novel therapeutic strategies for many diseases that have Fn14-overexpressing cells in affected tissues. The aims of this review are: 1) to present the main results on TWEAK/Fn14 regulation of cell fates, 2) to analyze the mechanism of the Fn14-TRAF2-TNFR axis, and 3) to summarize the potential strategies in the pharmacologic targeting of this axis.

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TNF and Ubiquitination

Kupka

Walczak

2017

Encyclopedia of Life Sciences

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Tumour necrosis factor (TNF) is a potent inflammatory cytokine. TNF is required to fight off infections but is also a crucial player in several pathological conditions including inflammatory bowel disease, psoriasis, rheumatoid arthritis and cancer. TNF‐induced inflammation can be the result of TNF‐induced gene activation but also cell death. TNF can activate gene induction via both of its receptors, TNF receptor 1 and 2 (TNFR1 and TNFR2), but induction of cell death occurs exclusively via TNFR1. Consequently, the TNFR1‐signalling complex (TNFR1‐SC) needs to be regulated which is also achieved by posttranslational modifications. Various components of the signalling complex are phosphorylated and/or ubiquitinated. Ubiquitination is the conjugation of the 7.6‐kDa protein ubiquitin to another protein and has emerged as a crucial posttranslational modification in many signalling pathways. Ubiquitination ensures correct complex formation and disassembly. An intriguing network of ubiquitin ligases, deubiquitinases and ubiquitin‐binding proteins forms a central part of TNFR1 signalling. Key Concepts TNF, via its receptor TNFR1, can trigger gene activation or cell death. TNF‐induced gene activation and also cell death can drive inflammatory diseases. Ubiquitin chains can be assembled by linking the C‐terminal glycine of ubiquitin to one of the seven lysine (K) residues or methionine 1 (M1) of another ubiquitin. Ubiquitin ligases regulate the signalling complex assembly by attaching ubiquitin chains, composed of different linkage types, to individual complex components. Specific ubiquitin‐binding proteins recognise different ubiquitin linkage types, thus enabling their recruitment to the signalling complex and to act as adaptors. Deubiquitinases can specifically remove certain linkage types in order to regulate the spatiotemporal assembly/disassembly of the signalling complex. Failure to regulate the ubiquitin system in TNFR1 signalling can be causative for excessive inflammation, pathological cell death and autoimmunity.

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TRAF2 multitasking in TNF receptor-induced signaling to NF-κB, MAP kinases and cell death

Cited by 179 publications

References 86 publications

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling

TNF and Ubiquitination

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