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1.
Nucleic Acids Res ; 43(14): 6983-93, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26101251

RESUMO

Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-κB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-κB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKγ to the IKK catalytic subunits, IKK-α and -ß, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and ß. Collectively, these results suggest that FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51.


Assuntos
Melanoma/metabolismo , NF-kappa B/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Linhagem Celular Tumoral , Humanos , Quinase I-kappa B/metabolismo , Melanoma/enzimologia , Domínios e Motivos de Interação entre Proteínas , Fator 2 Associado a Receptor de TNF/metabolismo , Proteínas de Ligação a Tacrolimo/química
2.
Nat Commun ; 6: 6074, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25606824

RESUMO

Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.


Assuntos
Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Animais , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Separação Celular , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Células Jurkat , Macrófagos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Orthomyxoviridae , Fenótipo , Fosforilação , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
3.
J Exp Med ; 211(8): 1689-702, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-24980047

RESUMO

Development of autoimmune diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), involves the inflammatory action of Th1 and Th17 cells, but the underlying signaling mechanism is incompletely understood. We show that the kinase TPL2 is a crucial mediator of EAE and is required for the pathological action of Th17 cells. TPL2 serves as a master kinase mediating the activation of multiple downstream pathways stimulated by the Th17 signature cytokine IL-17. TPL2 acts by linking the IL-17 receptor signal to the activation of TAK1, which involves a dynamic mechanism of TPL2-TAK1 interaction and TPL2-mediated phosphorylation and catalytic activation of TAK1. These results suggest that TPL2 mediates TAK1 axis of IL-17 signaling, thereby promoting autoimmune neuroinflammation.


Assuntos
Autoimunidade/imunologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Sistema Hematopoético/patologia , Humanos , Ativação Linfocitária/imunologia , MAP Quinase Quinase Quinases/deficiência , Camundongos Knockout , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas/deficiência , Tolerância a Radiação , Células Th17/imunologia
4.
Immunity ; 40(5): 692-705, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24792914

RESUMO

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.


Assuntos
Sistema ASC de Transporte de Aminoácidos/imunologia , Glutamina/metabolismo , Complexos Multiproteicos/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transferência Adotiva , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Proteína 10 de Linfoma CCL de Células B , Transporte Biológico , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Antígenos CD28/imunologia , Caspases/metabolismo , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática/imunologia , Humanos , Inflamação/imunologia , Interleucina-2/biossíntese , Células Jurkat , Leucina/metabolismo , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/imunologia , Células Th1/imunologia
5.
Nat Med ; 19(5): 595-602, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23603814

RESUMO

Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor-associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.


Assuntos
Sistema Nervoso Central/fisiologia , Regulação da Expressão Gênica , Inflamação/patologia , Microglia/metabolismo , Proteínas Nucleares/fisiologia , Fator 3 Associado a Receptor de TNF/metabolismo , Animais , Células da Medula Óssea/citologia , Feminino , Fibroblastos/citologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Ubiquitina-Proteína Ligases
6.
Nature ; 494(7437): 371-4, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23334419

RESUMO

The non-canonical NF-κB pathway forms a major arm of NF-κB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-κB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyperactivation of non-canonical NF-κB. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. Consequently, the OTUD7B deficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-induced non-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.


Assuntos
Endopeptidases/metabolismo , NF-kappa B/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Ubiquitinação , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Bactérias/imunologia , Células Cultivadas , Endopeptidases/deficiência , Endopeptidases/genética , Feminino , Fibroblastos , Células HEK293 , Homeostase , Humanos , Intestinos/imunologia , Masculino , Camundongos , Proteólise , Receptores de Superfície Celular/metabolismo
7.
Proc Natl Acad Sci U S A ; 109(49): 20083-8, 2012 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-23169648

RESUMO

T-cell receptor-α (TCRα) rearrangement in CD4(+)CD8(+) double-positive immature thymocytes is a prerequisite for production of αß T cells and invariant natural killer T cells. This developmental event is regulated by the TCRα enhancer (Eα), which induces chromatin modification and recruitment of the recombination-activating proteins Rag1 and Rag2. However, the molecular mechanism underlying the activation and long-range action of Eα remains incompletely understood. We show here that the chromatin-modifying factor TRIM28 is highly expressed in double-positive thymocytes and persistently phosphorylated at serine 473. TRIM28 binds to Eα and induces histone 3 lysine 4 trimethylation in the Eα and distant regions of the TCRα locus, coupled with recruitment of Rag proteins. T-cell-conditional ablation of TRIM28 impaired TCRα gene rearrangement and compromised the development of αß T cells and invariant natural killer T cells. These findings establish TRIM28 as a unique regulator of thymocyte development and highlight an epigenetic mechanism involving TRIM28-mediated active chromatin modification in the TCRα locus.


Assuntos
Diferenciação Celular/imunologia , Montagem e Desmontagem da Cromatina/fisiologia , Elementos Facilitadores Genéticos/genética , Células T Matadoras Naturais/citologia , Proteínas Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Proteínas Repressoras/metabolismo , Subpopulações de Linfócitos T/citologia , Animais , Imunoprecipitação da Cromatina , Metilação de DNA , Citometria de Fluxo , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Immunoblotting , Camundongos , Camundongos Transgênicos , Células T Matadoras Naturais/imunologia , Fosforilação , Subpopulações de Linfócitos T/imunologia , Timócitos/metabolismo , Proteína 28 com Motivo Tripartido
8.
Nat Immunol ; 13(11): 1101-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23023393

RESUMO

Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.


Assuntos
Glomerulonefrite por IGA/genética , Imunoglobulina A/genética , Switching de Imunoglobulina/genética , NF-kappa B/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Deleção de Genes , Regulação da Expressão Gênica/imunologia , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , Fosforilação , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Transdução de Sinais
9.
Cell Mol Immunol ; 9(2): 113-22, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22307041

RESUMO

E3 ubiquitin ligases play a crucial role in regulating immune receptor signaling and modulating immune homeostasis and activation. One emerging family of such E3s is the Pelle-interacting (Peli) proteins, characterized by the presence of a cryptic forkhead-associated domain involved in substrate binding and an atypical RING domain mediating formation of both lysine (K) 63- and K48-linked polyubiquitin chains. A well-recognized function of Peli family members is participation in the signal transduction mediated by Toll-like receptors (TLRs) and IL-1 receptor. Recent gene targeting studies have provided important insights into the in vivo functions of Peli1 in the regulation of TLR signaling and inflammation. These studies have also extended the biological functions of Peli1 to the regulation of T-cell tolerance. Consistent with its immunoregulatory functions, Peli1 responds to different immune stimuli for its gene expression and catalytic activation. In this review, we discuss the recent progress, as well as the historical perspectives in the regulation and biological functions of Peli.


Assuntos
Proteínas Nucleares/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Humanos , Tolerância Imunológica , Imunomodulação , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia
10.
Nat Immunol ; 12(10): 1002-9, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21874024

RESUMO

T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-ß (TGF-ß). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.


Assuntos
Autoimunidade , Ativação Linfocitária , Proteínas Nucleares/fisiologia , Linfócitos T/imunologia , Animais , Antígenos CD28/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-rel/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Reguladores/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Ubiquitina-Proteína Ligases , Ubiquitinação
11.
Proc Natl Acad Sci U S A ; 108(31): 12827-32, 2011 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-21768353

RESUMO

Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-κB-inducing kinase (NIK), a central component of the noncanonical NF-κB signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-κB. Our findings suggest that the noncanonical NF-κB pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.


Assuntos
NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Feminino , Citometria de Fluxo , Expressão Gênica , Células HEK293 , Humanos , Imunização/métodos , Ligante Coestimulador de Linfócitos T Induzíveis , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/genética , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Auxiliares-Indutores/metabolismo
12.
Sci Signal ; 4(161): ra11, 2011 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-21343618

RESUMO

The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. Members of the nuclear factor κB (NF-κB) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the κB site and the IFN response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-κB p50 homodimer as a regulator of IRF responses. Unbiased genome-wide expression and biochemical and structural analyses revealed that the p50 homodimer repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences. Mathematical modeling predicted that the p50 homodimer might enforce the stimulus specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-ß was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE-containing IFNß enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-ß in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-κB p50 homodimer in enforcing the specificity of the cellular response to pathogens by binding to a subset of IRE sequences alters our understanding of how the NF-κB and IRF signaling systems cooperate to regulate antimicrobial immunity.


Assuntos
Imunidade Inata , Interferons/metabolismo , Subunidade p50 de NF-kappa B/fisiologia , Animais , Sequência de Bases , Linhagem Celular , Sondas de DNA , Humanos , Camundongos , Camundongos Endogâmicos C57BL
13.
EMBO J ; 29(9): 1600-12, 2010 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-20224552

RESUMO

Natural killer T (NKT) cells modulate immune responses against pathogens and tumours, as well as immunological tolerance. We show here that CYLD, a tumour suppressor with deubiquitinase function, has a pivotal and cell-intrinsic function in NKT cell development. Unlike other known NKT regulators, CYLD is dispensable for intrathymic NKT cell maturation but is obligatory for the survival of immature NKT cells. Interestingly, CYLD deficiency impairs the expression of ICOS, a costimulatory molecule required for the survival and homeostasis of NKT cells, and this molecular defect is associated with attenuated response to an NKT-survival cytokine, IL-7, due to reduced expression of IL-7 receptor. We show, for the first time, that IL-7 induces the expression of ICOS in NKT cells, which is largely dependent on CYLD. Interestingly, loss of CYLD causes constitutive NF-kappaB activation in developing NKT cells, which contributes to their defective IL-7 response and attenuated ICOS expression. These findings establish CYLD as a critical regulator of NKT cell development and provide molecular insights into this novel function of CYLD.


Assuntos
Cisteína Endopeptidases/metabolismo , Linfopoese , Células T Matadoras Naturais/citologia , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Interleucina-7/imunologia , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/imunologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Fenótipo , Proteínas/imunologia , Proteínas/metabolismo , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo
14.
Sci Signal ; 3(105): ra4, 2010 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-20086239

RESUMO

Our adaptive immune system induces distinct responses to different pathogens because of the functional plasticity of dendritic cells (DCs); however, how DCs program unique responses remains unclear. Here, we found that the cytokine thymic stromal lymphopoietin (TSLP) potently transduced a unique T helper type 2 (T(H)2)-inducing compound signal in DCs. Whereas activation of nuclear factor kappaB (predominantly p50) drove DCs to produce OX40L to induce T(H)2 differentiation, the activation of signal transducer and activator of transcription 6 (STAT6) triggered DCs to secrete chemokines necessary for the recruitment of T(H)2 cells. In addition, TSLP signaling limited the activation of STAT4 and interferon regulatory factor 8 (IRF-8), which are essential factors for the production of the T(H)1-polarizing cytokine interleukin-12 (IL-12). By contrast, Toll-like receptor ligands and CD40 ligand did not activate STAT6 in myeloid DCs, but instead increased the abundance of STAT4 and IRF-8 to induce T(H)1 responses through the production of IL-12. Therefore, we propose that the functional plasticity of DCs relies on elaborate signal codes that are generated by different stimuli.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Citocinas/imunologia , Humanos , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , NF-kappa B/imunologia , Ligante OX40/metabolismo , Fatores de Transcrição STAT/metabolismo , Células Th2/imunologia
15.
Proc Natl Acad Sci U S A ; 106(39): 16776-81, 2009 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-19805372

RESUMO

Mucosal dendritic cells have been implicated in the capture, storage, and transmission of HIV to CD4(+) T cells as well as in the promotion of HIV replication in activated CD4(+) T cells during the cognate T-cell and DC interaction. We report that HIV induces human genital mucosal epithelial cells to produce thymic stromal lymphopoietin (TSLP) via activation of the NFkappaB signaling pathway. The TSLP secreted by HIV exposed epithelial cells activated DC, which promoted proliferation and HIV-1 replication of co-cultured autologous CD4(+) T cells. In rhesus macaques, we observed dramatic increases in TSLP expression concurrent with an increase in viral replication in the vaginal tissues within the first 2 weeks after vaginal SIV exposure. These data suggest that HIV-mediated TSLP production by mucosal epithelial cells is a critical trigger for DC-mediated amplification of HIV-infection in activated CD4(+) T cells. The cross talk between mucosal epithelial cells and DC, mediated by HIV-induced TSLP, may be an important mechanism for the high rate of HIV infection in women through the vaginal mucosa.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Células Dendríticas/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , HIV-1/fisiologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Feminino , HIV-1/patogenicidade , Humanos , Macaca mulatta , NF-kappa B/metabolismo , Vírus da Imunodeficiência Símia/patogenicidade
16.
Nat Immunol ; 10(10): 1089-95, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19734906

RESUMO

Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas Nucleares/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Linfócitos B/imunologia , Western Blotting , Citocinas/biossíntese , Ensaio de Desvio de Mobilidade Eletroforética , Ativação Enzimática/imunologia , Feminino , Citometria de Fluxo , Proteínas Ativadoras de GTPase/imunologia , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Quinase I-kappa B/imunologia , Quinase I-kappa B/metabolismo , Imunoprecipitação , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo , Ubiquitina-Proteína Ligases , Ubiquitinação
17.
J Immunol ; 182(5): 3131-8, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19234210

RESUMO

Transcription factor NF-kappaB is regulated by a family of inhibitors, IkappaBs, as well as the NF-kappaB1 and NF-kappaB2 precursor proteins, p105 and p100. Although the different NF-kappaB inhibitors can all inhibit NF-kappaB in vitro, their physiological functions are incompletely understood. In this study, we demonstrate that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice lacking p105, but expressing the mature NF-kappaB1 p50, spontaneously develop intestinal inflammation with features of human inflammatory bowel disease. This inflammatory disorder occurs under specific pathogen-free conditions and critically involves T cells. Consistently, the p105-deficient mice have reduced frequency of naive T cells and increased frequency of memory/effector T cells in the peripheral lymphoid organs. Although p105 is dispensable for the production of immunosuppressive regulatory T cells, p105 deficiency renders CD4 T cells more resistant to Treg-mediated inhibition. We further show that the loss of p105 results in hyperproduction of Th17 subset of inflammatory T cells. Together, these findings suggest a critical role for NF-kappaB1 p105 in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation.


Assuntos
Mediadores da Inflamação/fisiologia , Subunidade p50 de NF-kappa B/fisiologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Doença Crônica , Homeostase/genética , Homeostase/imunologia , Imunofenotipagem , Mediadores da Inflamação/antagonistas & inibidores , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/deficiência , Subunidade p50 de NF-kappa B/genética , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
18.
J Biol Chem ; 283(27): 18621-6, 2008 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-18467330

RESUMO

The IkappaB kinase (IKK)-related kinases, IKKepsilon and TBK1, participate in the induction of type I interferons (IFNs) during viral infections. Deregulated activation of IKKepsilon and TBK1 also contributes to the abnormal cell survival and transformation. However, how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role in preventing aberrant activation of IKKepsilon/TBK1. CYLD deficiency causes constitutive activation of IKKepsilon/TBK1, which is associated with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKKepsilon/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function, CYLD potently inhibits RIG-I-mediated activation of the IFN-beta promoter. These findings establish CYLD as a key negative regulator of IKKepsilon/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.


Assuntos
Cisteína Endopeptidases/metabolismo , Quinase I-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Viroses/metabolismo , Animais , Sobrevivência Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Cisteína Endopeptidases/genética , Ativação Enzimática/genética , Quinase I-kappa B/genética , Interferon beta/genética , Interferon beta/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Ubiquitinação/genética , Viroses/genética
19.
J Clin Invest ; 118(5): 1858-66, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18382763

RESUMO

Osteoclastogenesis is a tightly regulated biological process, and deregulation can lead to severe bone disorders such as osteoporosis. The regulation of osteoclastic signaling is incompletely understood, but ubiquitination of TNF receptor-associated factor 6 (TRAF6) has recently been shown to be important in mediating this process. We therefore investigated the role of the recently identified deubiquitinating enzyme CYLD in osteoclastogenesis and found that mice with a genetic deficiency of CYLD had aberrant osteoclast differentiation and developed severe osteoporosis. Cultured osteoclast precursors derived from CYLD-deficient mice were hyperresponsive to RANKL-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. We assessed the expression pattern of CYLD and found that it was drastically upregulated during RANKL-induced differentiation of preosteoclasts. Furthermore, CYLD negatively regulated RANK signaling by inhibiting TRAF6 ubiquitination and activation of downstream signaling events. Interestingly, we found that CYLD interacted physically with the signaling adaptor p62 and thereby was recruited to TRAF6. These findings establish CYLD as a crucial negative regulator of osteoclastogenesis and suggest its involvement in the p62/TRAF6 signaling axis.


Assuntos
Reabsorção Óssea/metabolismo , Cisteína Endopeptidases/metabolismo , Osteoclastos/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/fisiologia , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular/fisiologia , Cisteína Endopeptidases/genética , Masculino , Camundongos , Camundongos Knockout , Osteoclastos/citologia , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Fator 6 Associado a Receptor de TNF/genética , Fatores de Transcrição/metabolismo , Ubiquitina/metabolismo
20.
Dev Cell ; 13(5): 705-16, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17981138

RESUMO

Spermatogenesis involves an early wave of germ cell apoptosis, which is required for maintaining the balance between germ cells and supporting Sertoli cells. However, the signaling mechanism regulating this apoptotic event is poorly defined. Here we show that genetic deficiency of Cyld, a recently identified deubiquitinating enzyme, attenuates the early wave of germ cell apoptosis and causes impaired spermatogenesis in mice. Interestingly, the loss of CYLD in testicular cells leads to activation of the transcription factor NF-kappaB and aberrant expression of antiapoptotic genes. We further show that CYLD negatively regulates a ubiquitin-dependent NF-kappaB activator, RIP1. CYLD binds to RIP1 and inhibits its ubiquitination and signaling function. These findings establish CYLD as a pivotal deubiquitinating enzyme (DUB) that regulates germ cell apoptosis and spermatogenesis and suggest an essential role for CYLD in controlling the RIP1/NF-kappaB signaling axis in testis.


Assuntos
Apoptose , Cisteína Endopeptidases/fisiologia , Células Germinativas/fisiologia , Espermatogênese , Animais , Cisteína Endopeptidases/genética , Proteínas Ativadoras de GTPase/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fosforilação , Transdução de Sinais , Ubiquitinação
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