Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Chau, Tieu-Lan; Gioia, Romain; Gatot, Jean-Stéphane; Patrascu, Felicia Alina; Carpentier, Isabelle; Chapelle, Jean-Paul; O’Neill, Luke A. J.; Beyaert, Rudi; Piette, Jacques; Chariot, Alain

doi:10.1016/j.tibs.2008.01.002

Cited by 207 publications

(172 citation statements)

References 85 publications

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“…In binding and activating IRF7, NF-B, JNK, and p38, LMP1 CTAR2 mimics an activated TLR 7,8,or 9 (23,24,30,38). Downstream of TLR 7, 8, or 9, IRF7 association with MyD88 may be critical for efficient receptor mediated IRF7 activation (22)(23)(24)30).…”

Section: Discussionmentioning

confidence: 99%

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IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1), a constitutively aggregated and activated pseudoreceptor, activates IFN regulatory factor 7 (IRF7) through RIP1. We now report that the LMP1 cytoplasmic carboxyl terminal amino acids 379 -386 bound IRF7 and activated IRF7. IRF7 activation required TRAF6 and RIP1, but not TRAF2 or TRAF3. LMP1 Y384YD386, which are required for TRADD and RIP1 binding and for NF-B activation, were not required for IRF7 binding, but were required for IRF7 activation, implicating signaling through TRADD and RIP1 in IRF7 activation. Association with active LMP1 signaling complexes was also critical for IRF7 activation because (i) a dominant-negative IRF7 bound to LMP1, blocked IRF7 association and activation, but did not inhibit LMP1 induced NF-B or TBK1 or Sendai virus-mediated IFN stimulated response element activation; and (ii) two different LMP1 transmembrane domain mutants, which fail to aggregate, each bound IRF7 and prevented LMP1 from binding and activating IRF7 in the same cell, but did not prevent NF-B activation. Thus, efficient IRF7 activation required association with LMP1 CTAR2 in proximity to LMP1 CTAR2 mediated kinase activation sites. LMP1 has a 24-aa cytoplasmic N-terminus, six hydrophobic transmembrane domains (amino acids 25 to 186) and a 200-aa cytoplasmic C-terminus (amino acids 187 to 386). The transmembrane domains induce LMP1 aggregation in plasma membrane lipid rafts and barges and constitutively activate two C-terminal cytoplasm signaling domains referred to as C-terminal activation regions (CTAR) or transformation effector sites (TES) 1 and 2, which were initially defined as amino acids 187-231 and 352-386, respectively (Fig. 1A) (2-9). CTAR1 amino acids 201 to 210 engage tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) 1, 3, 2, and 5 and CTAR2 amino acids 376-386 engage TNFRassociated death domain proteins TRADD and RIP1 (4-12). Both signaling domains activate NF-B, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, thereby altering cell gene expression, cell survival, and immune responses (13-17).LMP1 also induces and activates IFN regulatory factor 7 (IRF7) (18-20), a critical transcription factor for type 1 IFN (IFN)-mediated innate and adaptive immune responses (21-24). IRF7 is comprised of DNA binding, constitutive activation, virus activated, inhibitory, and signal response domains and is activated by serine 477 and 479 phosphorylation (25). Although IRF7 is expressed at low levels in nonstimulated cells, IRF7 is critical for type I IFN expression, particularly in plasmacytoid dendritic cells (24,26,27). Toll-like receptor activation, LMP1 expression, viral infection, and other signals that activate IRF3 and induce IFN ␤ (IFN␤), can up-regulate IRF7 expression (18, 21-24, 28, 29). IRF7 can bind and localize to MyD88 until ligand-activated Toll-like receptors 7, 8, or 9 engage MyD88 and activate IRF7, which enters the nucleus and up-regulates IFN stimulated response elements (ISREs) to activate I...

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Section: Discussionmentioning

confidence: 99%

“…IRF7 can bind to TRAF3 and to RIP1, which may recruit TBK1 or IKK to phosphorylate and activate IRF7 (20,23,24,(38)(39)(40). TRADD and to a lesser extent RIP1 directly interact with LMP1 CTAR2.…”

Section: Discussionmentioning

confidence: 99%

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Lys 63 -ubiquitinated signaling proteins are then recognized by specific ubiquitin-binding scaffolding proteins that assemble and activate downstream kinases (e.g. Lys 63 -ubiquitinated RIP1 (receptor-interacting protein 1) is recognized by the IKK␣/IKK␤ adaptor NEMO) (28).…”

Section: Molecular Mechanism Of A20 Activitymentioning

confidence: 99%

A20: Central Gatekeeper in Inflammation and Immunity

Coornaert

Carpentier

Beyaert

2009

Journal of Biological Chemistry

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287

251

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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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“…TBK1 and IKKε interact via their C termini with TANK, NFκB activating kinase (NAK)-associated protein 1 (NAP1) and similar to NAP1 TBK1 adaptor (Sintbad) (17)(18)(19), but only TBK1 interacts with optineurin (20). It has therefore been suggested that distinct forms of the IKK-related kinases may be present in cells, each comprising a catalytic subunit and a different regulatory subunit, which are involved in regulating different aspects of innate immunity (21). The recent characterization of the TANK −/− mouse led to the unexpected finding that TANK is not required for the production of IFNβ in response to viral infection, but instead is required to limit MyD88-dependent TLR signaling and so prevent the development of autoimmune nephritis (1).…”

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confidence: 99%

The TRAF-associated protein TANK facilitates cross-talk within the IκB kinase family during Toll-like receptor signaling

Clark

Takeuchi

Akira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

106

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Toll-like receptor (TLR) ligands that signal via TIR-domain-containing adapter-inducing IFNβ (TRIF) activate the IκB kinase (IKK)-related kinases, TRAF associated NFκB activator (TANK)-binding kinase-1 (TBK1) and IKKε, which then phosphorylate IRF3 and induce the production of IFNβ. Here we show that TBK1 and IKKε are also activated by TLR ligands that signal via MyD88. Notably, the activation of IKKε is rapid, transient, and it precedes a more prolonged activation of TBK1. The MyD88-and TRIF-dependent signaling pathways activate the IKK-related kinases by two signaling pathways. One is mediated by the canonical IKKs, whereas the other culminates in the autoactivation of the IKK-related kinases. Once activated, TBK1/IKKε then phosphorylate and inhibit the canonical IKKs. The negative regulation of the canonical IKKs by the IKK-related kinases occurs in both the TRIF-and MyD88-dependent TLR pathways, whereas IRF3 phosphorylation is restricted to the TRIF-dependent signaling pathway. We have discovered that the activation of IKKε is abolished, the activation of TBK1 is reduced, and the interaction between the IKK-related kinases and the canonical IKKs is suppressed in TANK −/− macrophages, preventing the IKK-related kinases from negatively regulating the canonical IKKs. In contrast, IRF3 phosphorylation and IFNβ production was normal in TANK −/− macrophages. Our results demonstrate a key role for TANK in enabling the canonical IKKs and the IKK-related kinases to regulate each other, which is required to limit the strength of TLR signaling and ultimately, prevent autoimmunity.

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Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Cited by 207 publications

References 85 publications

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

A20: Central Gatekeeper in Inflammation and Immunity

The TRAF-associated protein TANK facilitates cross-talk within the IκB kinase family during Toll-like receptor signaling

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