Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling

Shembade, Noula; Harhaj, Nicole S.; Liebl, Daniel J.; Harhaj, Edward W.

doi:10.1038/sj.emboj.7601823

Cited by 178 publications

(177 citation statements)

References 49 publications

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“…How the negative regulatory effect of upregulated A20 on NF-κB signaling is disrupted in gliomas, however, remains unclear. Given that A20 does not have specificity for K63-linked polyubiquitin [29,30,36,37], have been proposed to participate in the NF-κB inhibitory effect of A20 through modulation of A20 activity. For example, ITCH has been found to terminate NF-κB signaling by controlling A20-mediated recruitment and inactivation of RIP1.…”

Section: Discussionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

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Section: Discussionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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“…The use of different molecules exerting similar functions allows the cell to specifically regulate the effect of for example TLR stimulation, leaving the effect of TNF-R1 signaling intact. Several examples of negative regulatory molecules interfering with NF-kB signaling in a receptor-specific way are already known, such as A20 [107], MyD88s [108,109] and TAX1BP1 [110,111]. Anti-TNF therapies (e.g.…”

Section: Discussionmentioning

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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“…More recently, TAX1BP1-deficient cells were shown to have a prolonged NF-B response to IL-1, LPS, and TNF treatment, which is associated with elevated ubiquitination of RIP1 and TRAF6 (56,57). More specifically, TAX1BP1 was shown to bind Lys 63 -ubiquitinated RIP1 and TRAF6, thus recruiting A20 to its substrate by forming a ternary complex (57).…”

Section: Regulation Of A20 Activitymentioning

confidence: 99%

A20: Central Gatekeeper in Inflammation and Immunity

Coornaert

Carpentier

Beyaert

2009

Journal of Biological Chemistry

290

253

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Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-B, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-B-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-B signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity. A20 (also known as TNFAIP3) was originally identified as a TNF 2 -inducible gene in human umbilical vein endothelial cells (1). Subsequent research demonstrated that A20 is also induced in many other cell types and by a wide range of other stimuli (reviewed in Ref. 2). Although A20 was originally characterized as an inhibitor of TNF-induced apoptosis (3), it has been most intensively studied as an inhibitor of NF-B activation. NF-B is a dimeric transcription factor that plays a key role in inflammation and immunity. A deregulated NF-B response has been associated with several autoimmune diseases and some cancers (4). The activity of NF-B is tightly regulated by interaction with inhibitory IB (inhibitor of B) proteins, which are regulated by IKK-mediated IB phosphorylation, followed by their ubiquitination and proteolysis, enabling the entry of NF-B into the nucleus. In most cases, the activation of NF-B is transient and cyclic upon continuous stimulation, which is due to specific negative feedback control systems such as the NF-Binducible synthesis of IB and A20 proteins (5). NF-B activation pathways are broadly classified as either canonical or noncanonical, depending on whether activation involves IB degradation or processing of the p100 NF-B precursor (4).The canonical pathway, which is the predominant NF-B signaling pathway, is activated by pro-inflammatory cytokines such as TNF and IL-1 and microbial components that activate, for example, TLRs or antigen receptors. The non-canonical pathway of NF-B activation operates mainly in B cells in response to a subset of TNFR family members, including the lymphotoxin-␤ receptor.Initial evidence for the NF-B inhibitory function of A20 came from several studies in which overexpression of A20 was shown to prevent NF-B activation in response to TNF and several other pro-inflammatory stimuli (reviewed in Ref.2). The observation that A20 expression is itself under the control of NF-B suggested its involvement in the negative feedback regulation of NF-B activation (6). This was eventually confirmed by the generation of A20-deficient mice, which show a sustained NF-B response and severe inflammation (7). The mechanism by which A20 inhibits NF-B activation remained a mystery for several years until it was recently found that A20 can act as a dual ubiquitin-editing enzyme.

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Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling

Cited by 178 publications

References 49 publications

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

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

A20: Central Gatekeeper in Inflammation and Immunity

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