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1.
Mol Cell ; 73(3): 413-428.e7, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30598363

RESUMO

Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.


Assuntos
Caspase 8/metabolismo , Instabilidade Cromossômica , Neoplasias do Colo/enzimologia , Fibroblastos/enzimologia , Mitose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Aneuploidia , Animais , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibroblastos/patologia , Células HT29 , Humanos , Inflamação/enzimologia , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Quinase 1 Polo-Like
2.
Nat Commun ; 9(1): 3910, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254289

RESUMO

The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.


Assuntos
Proteínas de Transporte/metabolismo , Dermatite/metabolismo , Proteína Ligante Fas/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Transporte/genética , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Células Cultivadas , Dermatite/genética , Peptídeos e Proteínas de Sinalização Intracelular , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Ubiquitina-Proteína Ligases/genética
3.
Nature ; 557(7703): 112-117, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29695863

RESUMO

The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death2-8. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9-11. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3-/-Casp8-/-Hoil-1-/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.


Assuntos
Proteínas de Transporte/metabolismo , Morte Celular , Desenvolvimento Embrionário , Hematopoese , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Animais , Proteínas de Transporte/química , Proteínas de Transporte/genética , Caspase 8/genética , Caspase 8/metabolismo , Morte Celular/genética , Perda do Embrião/genética , Desenvolvimento Embrionário/genética , Células Endoteliais/citologia , Feminino , Hematopoese/genética , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos , Proteínas Quinases/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética
4.
Nat Commun ; 7: 13353, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857075

RESUMO

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.


Assuntos
Diferenciação Celular/fisiologia , Homeostase/fisiologia , Linfócitos T/fisiologia , Timo/citologia , Ubiquitina/metabolismo , Animais , Sequência de Bases , Células Cultivadas , Biologia Computacional , Regulação da Expressão Gênica/fisiologia , Genótipo , Camundongos , Multimerização Proteica , Processamento de Proteína Pós-Traducional , RNA/genética , Análise de Sequência de RNA , Linfócitos T/classificação , Ubiquitina/química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
5.
J Exp Med ; 213(12): 2671-2689, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27810922

RESUMO

The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.


Assuntos
Síndromes de Imunodeficiência/metabolismo , Inflamação/patologia , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Dermatite/patologia , Inativação Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/imunologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Poli I-C/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/deficiência
6.
Cell Mol Life Sci ; 73(11-12): 2165-76, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27066894

RESUMO

Tumor necrosis factor (TNF) is a master pro-inflammatory cytokine, and inappropriate TNF signaling is implicated in the pathology of many inflammatory diseases. Ligation of TNF to its receptor TNFR1 induces the transient formation of a primary membrane-bound signaling complex, known as complex I, that drives expression of pro-survival genes. Defective complex I activation results in induction of cell death, in the form of apoptosis or necroptosis. This switch occurs via internalization of complex I components and assembly and activation of secondary cytoplasmic death complexes, respectively known as complex II and necrosome. In this review, we discuss the crucial regulatory functions of ubiquitination-a post-translational protein modification consisting of the covalent attachment of ubiquitin, and multiples thereof, to target proteins-to the various steps of TNFR1 signaling leading to necroptosis.


Assuntos
Apoptose/fisiologia , Necrose/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação/fisiologia , Animais , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais
7.
Trends Cell Biol ; 26(6): 445-461, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26877205

RESUMO

The kinase RIPK1 is an essential signaling node in various innate immune signaling pathways being most extensively studied in the TNFR1 signaling pathway. TNF signaling can result in different biological outcomes including gene activation and cell death induction in the form of apoptosis or necroptosis. RIPK1 is believed to be crucial for regulating the balance between these opposing outcomes. It is therefore not surprising that RIPK1 is highly regulated, most notably by phosphorylation, ubiquitination, and their respective reversals. In this review, we discuss the biological functions of RIPK1 within the context of TNFR1 signaling. Finally, we discuss recent advances in the knowledge on three ubiquitin E3 ligases that exert regulatory functions on RIPK1 signaling: cIAP1, cIAP2, and LUBAC.


Assuntos
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo , Animais , Morte Celular , Humanos , Ubiquitina-Proteína Ligases/metabolismo
8.
Elife ; 32014 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-25443632

RESUMO

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.


Assuntos
Inflamação/metabolismo , Inflamação/patologia , Proteínas do Tecido Nervoso/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Animais , Caspase 3/metabolismo , Caspase 8/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Doença Crônica , Citoproteção/efeitos dos fármacos , Dermatite/metabolismo , Dermatite/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Heterozigoto , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Células Mieloides/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
9.
Cell Rep ; 9(1): 153-165, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25284787

RESUMO

Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-α (LT-α), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP. Finally, we show that HOIP's catalytic activity is necessary for preventing TNF-induced cell death. Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death.


Assuntos
Perda do Embrião/metabolismo , Células Endoteliais/citologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Perda do Embrião/genética , Embrião de Mamíferos , Células Endoteliais/metabolismo , Feminino , Linfotoxina-alfa/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Saco Vitelino/irrigação sanguínea
10.
Proc Natl Acad Sci U S A ; 110(29): 12024-9, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23818611

RESUMO

Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.


Assuntos
Apoptose/fisiologia , Ciclofilinas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Necrose/fisiopatologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Traumatismo por Reperfusão/complicações , Animais , Linhagem Celular , Peptidil-Prolil Isomerase F , Ciclofilinas/genética , Primers do DNA/genética , Genótipo , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poro de Transição de Permeabilidade Mitocondrial , Necrose/etiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
11.
Mol Cell ; 43(3): 432-48, 2011 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-21737329

RESUMO

A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ∼2MDa cell death-inducing platform, referred to as "Ripoptosome." It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells.


Assuntos
Apoptose/fisiologia , Caspase 8/fisiologia , Dano ao DNA , Proteína de Domínio de Morte Associada a Fas/fisiologia , Proteínas Inibidoras de Apoptose/genética , Complexo de Proteínas Formadoras de Poros Nucleares/fisiologia , Proteínas de Ligação a RNA/fisiologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/fisiologia , Caspase 8/química , Caspase 8/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Etoposídeo/farmacologia , Proteína de Domínio de Morte Associada a Fas/química , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/fisiologia , Ligantes , Mitocôndrias/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais
12.
Nat Cell Biol ; 10(11): 1309-17, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18931663

RESUMO

The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-kappaB signalling and cell survival. The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation. Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-alpha-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2-MALT1 to activate NF-kappaB. Our data suggest that the UBA domain of cIAP2-MALT1 stimulates NF-kappaB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2-MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2-MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-kappaB signalling and oncogenesis.


Assuntos
Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/metabolismo , NF-kappa B/genética , Neoplasias/genética , Ubiquitina/metabolismo , Apoptose/genética , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular , Sobrevivência Celular/genética , Genes Reporter , Glutationa Transferase/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/genética , Rim/citologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Luciferases/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Neoplasias/patologia , Plasmídeos , Ligação Proteica , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Transfecção , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina/genética
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