Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The zinc finger protein A20 is encoded by an immediate early response gene whose expression is induced by different inflammatory stimuli, including interleukin-1 (IL-1). Gene induction by IL-1 is mediated by activation of the transcription factor NF-kappaB, and requires the signal adapter protein TRAF6. The latter interacts with the NF-kappaB-inducing kinase NIK, which is believed to be part of the IkappaB kinase complex. Expression of A20 potently inhibits IL-1-induced NF-kappaB activation by an unknown mechanism. Inhibition of IL-1-induced NF-kappaB activation was found to be mediated by the C-terminal zinc finger-containing domain of A20. More importantly, we present evidence that A20 interferes with IL-1-induced NF-kappaB activation at the level of TRAF6, upstream of NIK. Moreover, A20 was shown to directly interact with TRAF6.
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PMID:The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. 992 91

The tumor necrosis factor (TNF) inducible protein A20 is a potent inhibitor of nuclear factor-kappaB (IkappaB)-mediated gene expression in response to TNF and several other stimuli. The C-terminal domain of A20 is characterized by seven zinc finger structures. Here, we show that a minimum of four zinc fingers is required to inhibit TNF-induced nuclear factor-kappaB (NF-kappaB) activation to a level that is comparable to that obtained with the wild-type A20 protein. However, there was no strict requirement for a particular zinc finger structure, since a mutant A20 protein containing only the first four zinc fingers was as potent as a mutant protein containing only the last four zinc fingers. A similar functional redundancy of the A20 zinc fingers was also observed for binding of A20 to a number of other proteins, including two novel NF-kappaB inhibitory proteins (ABIN-1, ABIN-2), A20 itself, the anti-apoptotic protein TXBP151, and a regulatory component of the IkappaB kinase complex, IKKgamma. Moreover, we demonstrate that complete loss of binding of any of these proteins correlates with complete loss of A20's ability to inhibit TNF-induced NF-kappaB activation. However, binding of IKKgamma as such is not sufficient for inhibition of NF-kappaB dependent gene expression in response to TNF.
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PMID:Functional redundancy of the zinc fingers of A20 for inhibition of NF-kappaB activation and protein-protein interactions. 1138 5

Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappa B activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified ZIN (zinc finger protein inhibiting NF-kappa B), a novel protein that specifically interacts with RIP. ZIN contains four RING-like zinc finger domains at the middle and a proline-rich domain at the C terminus. Overexpression of ZIN inhibits RIP-, IKK beta-, TNF-, and IL1-induced NF-kappa B activation in a dose-dependent manner in 293 cells. Domain mapping experiments indicate that the RING-like zinc finger domains of ZIN are required for its interaction with RIP and inhibition of RIP-mediated NF-kappa B activation. Overexpression of ZIN also potentiates RIP- and TNF-induced apoptosis. Moreover, immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF- and IL1-induced NF-kappa B activation pathways.
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PMID:A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation. 1185 71

To gain insight in the subcellular localization of tumor necrosis factor receptor-associated factor (TRAF4) we analyzed GFP chimeras of full-length TRAF4 and various deletion mutants derived thereof. While TRAF4-GFP (T4-GFP) was clearly localized in the cytoplasm, the N-terminal deletion mutant, T4(259-470), comprising the TRAF domain of the molecule, and a C-terminal deletion mutant consisting mainly of the RING and zinc finger domains of TRAF4 were both localized predominantly to the nucleus. Passive nuclear localization of T4(259-470) can be ruled out as the TRAF domain of TRAF4 was sufficient to form high molecular weight complexes. T4(259-470) recruited full-length TRAF4 into the nucleus whereas TRAF4 was unable to change the nuclear localization of T4(259-470). Thus, it seems that individual T4(259-470) mutant molecules are sufficient to direct the respective TRAF4-T4(259-470) heteromeric complexes into the nucleus. In cells forming cell-cell contacts, TRAF4 was recruited to the sites of contact via its C-TRAF domain. The expression of some TRAF proteins is regulated by the NF-kappaB pathway. Thus, we investigated whether this pathway is also involved in the regulation of the TRAF4 gene. Indeed, in primary T-cells and Jurkat cells stimulated with the NF-kappaB inducers TNF or phorbol 12-myristate 13-acetate (PMA), TRAF4-mRNA was rapidly up-regulated. In Jurkat T-cells deficient for I-kappaB kinase gamma (IKKgamma, also known as NEMO), an essential component of the NF-kappaB-inducing-IKK complex, induction of TRAF4 was completely inhibited. In cells deficient for RIP (receptor interactive protein), an essential signaling intermediate of TNF-dependent NF-kappaB activation, TNF-, but not PMA-induced up-regulation of TRAF4 was blocked. These data suggest that activation of the NF-kappaB pathway is involved in up-regulation of TRAF4 in T-cells.
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PMID:Intracellular localization and transcriptional regulation of tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4). 1235 13

Transcription factor NF-kappaB plays a pivotal regulatory role in the genetic programs for cell cycle progression and inflammation. Nuclear translocation of NF-kappaB is controlled by an inducible protein kinase called IKK, which earmarks cytoplasmic inhibitors of NF-kappaB for proteolytic destruction. IKK contains two structurally related catalytic subunits termed IKKalpha and IKKbeta as well as a noncatalytic subunit called IKKgamma/NEMO. Mutations in the X-linked gene encoding IKKgamma can interfere with NF-kappaB signaling and lead to immunodeficiency disease. Although its precise mechanism of action remains unknown, IKKgamma is phosphorylated in concert with the induction of NF-kappaB by the viral oncoprotein Tax and the proinflammatory cytokine tumor necrosis factor alpha (TNF). We now demonstrate that TNF-induced phosphorylation of IKKgamma is blocked in cells deficient for IKKbeta but not IKKalpha. Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376 following the enforced expression of either the Tax oncoprotein or the type 1 TNF receptor. Inducible phosphorylation of IKKgamma is attenuated following the deletion of its COOH-terminal zinc finger domain (amino acids 397-419), a frequent target for mutations that occur in IKKgamma-associated immunodeficiencies. As such, IKKbeta-mediated phosphorylation of IKKgamma at these specific serine targets may facilitate proper regulation of NF-kappaB signaling in the immune system.
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PMID:In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase. 1265 30

NEMO (NF-kappaB essential modifier)/IKKgamma (IkappaB kinase-gamma) is required for the activation of the IkappaB kinase complex (IKK) by inflammatory stimuli such as tumor necrosis factor (TNF-alpha). Here we show that TNF-alpha stimulates the ubiquitination of NEMO in a manner that does not appear to target it for degradation and that is impaired by mutations in the NEMO zinc finger. Mutations of the zinc finger are found in patients with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID) and lead to the impairment of TNF-alpha-stimulated IKK phosphorylation and activation. In addition, the ubiquitination of NEMO is mediated by c-IAP1, an inhibitor of apoptosis protein that is a component of the TNF receptor signaling complex. Thus, the ubiquitination of NEMO mediated by c-IAP1 likely plays an important role in the activation of IKK by TNF-alpha. Also, defective NEMO ubiquitination may be responsible for the impaired cellular NF-kappaB signaling found in patients with HED-ID.
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PMID:A role for NF-kappaB essential modifier/IkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. 1286 25

TRAF2 is a RING finger protein that regulates the cellular response to stress and cytokines by controlling JNK, p38 and NF-kappaB signaling cascades. Here, we demonstrate that TRAF2 ubiquitination is required for TNFalpha-induced activation of JNK but not of p38 or NF-kappaB. Intact RING and zinc finger domains are required for TNFalpha-induced TRAF2 ubiquitination, which is also dependent on Ubc13. TRAF2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of JNK. Inhibition of Ubc13 expression by RNAi resulted in inhibition of TNFalpha-induced TRAF2 translocation and impaired activation of JNK but not of IKK or p38. TRAF2 aggregates in the cytoplasm, as seen in Hodgkin-Reed-Sternberg lymphoma cells, resulting in constitutive NF-kappaB activity but failure to activate JNK. These findings demonstrate that the TRAF2 RING is required for Ubc13-dependent ubiquitination, resulting in translocation of TRAF2 to an insoluble fraction and activation of JNK, but not of p38 or NF-kappaB. Altogether, our findings highlight a novel mechanism of TRAF2-dependent activation of diverse signaling cascades that is impaired in Hodgkin-Reed-Sternberg cells.
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PMID:Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-kappaB. 1471 52

The transcription factor NFkappaB plays important roles in immune regulation, inflammatory responses, and anti-apoptosis. Activation of NFkappaB requires the activity of IkappaB kinase, a kinase complex that contains two catalytic subunits, IKKalpha and IKKbeta, and a non-enzymatic regulatory subunit, IKKgamma. To understand how NFkappaB activation is regulated at the IKKgamma level, we searched for IKKgamma-interacting proteins by the yeast two-hybrid system. This search identified ZNF216, a zinc finger protein with unknown biological functions. ZNF216 contains an A20-like zinc finger domain (ZnF-A20) at its N terminus and an AN1-like domain (ZnF-AN1) at its C terminus. Similar to A20, ZNF216 interacted with IKKgamma, RIP, and TRAF6 in co-immunoprecipitation experiments. Domain mapping experiments indicated that the ZnF-A20 domain was responsible for interacting with IKKgamma and RIP, whereas the ZnF-AN1 domain interacted with TRAF6. ZNF216 inhibited NFkappaB activation triggered by overexpression of RIP and TRAF6 but not of p65. ZNF216 also inhibited tumor necrosis factor (TNF)-, interleukin-1-, and Toll-like receptor 4-induced NFkappaB activation in a dose-dependent manner. The ZnF-A20 domain was essential for ZNF216-mediated inhibition of NFkappaB activation. The ZnF-A20 and ZnF-AN1 domains of ZNF216 could interact with each other, whereas ZNF216 could form homo-oligomers or hetero-oligomers with A20. Unlike A20, which inhibits TNF-induced apoptosis, overexpression of ZNF216 sensitized cells to TNF-induced apoptosis. Our findings suggest that ZNF216 and A20 have redundant and distinct roles in regulating NFkappaB activation and apoptosis.
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PMID:ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation. 1475 97

The activation of NF-kappaB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains. Here we present evidence that TAB2 and TAB3 are receptors that bind preferentially to lysine 63-linked polyubiquitin chains through a highly conserved zinc finger (ZnF) domain. Mutations of the ZnF domain abolish the ability of TAB2 and TAB3 to bind polyubiquitin chains, as well as their ability to activate TAK1 and IKK. Significantly, replacement of the ZnF domain with a heterologous ubiquitin binding domain restored the ability of TAB2 and TAB3 to activate TAK1 and IKK. We also show that TAB2 binds to polyubiquitinated RIP following TNFalpha stimulation. These results indicate that polyubiquitin binding domains represent a new class of signaling domains that regulate protein kinase activity through a nonproteolytic mechanism.
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PMID:TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. 1532 70

Activation of the interferon regulatory factors (IRFs) 3 and 7 transcription factors is essential for the induction of type I interferon (IFN) and development of the innate antiviral response. Retinoic acid-inducible gene I has been shown to contribute to virus-induced IFN production independent of the Toll-like receptor pathways in response to a variety of RNA viruses and double-stranded RNA. In the present study, we demonstrate that the NF-kappaB-inducible, anti-apoptotic protein A20 efficiently blocks RIG-I-mediated activation of NF-kappaB-, IRF-3-, and IRF-7-dependent promoters but only weakly interferes with TRIF-TLR-3-mediated IFN activation. Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding. The level of A20 inhibition was upstream of the TBK1/IKKepsilon kinases that phosphorylate IRF3 and IRF7 and paradoxically, A20 selectively degraded the TRIF protein but not RIG-I. A20 possesses two ubiquitin-editing domains, an N-terminal deubiquitination domain and a C-terminal ubiquitin ligase domain consisting of seven zinc finger domains. Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression. Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20. These results suggest that the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state.
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PMID:Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. 1630 43


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