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1.
Cell ; 168(5): 789-800.e10, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28235196

RESUMO

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Lipopolissacarídeos/metabolismo , Glicoproteínas de Membrana/deficiência , Receptores de Interleucina-1/deficiência , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/metabolismo , Imunidade Adaptativa , Criança , Feminino , Fibroblastos/metabolismo , Humanos , Imunidade Inata , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Linhagem , Fagócitos/metabolismo , Mutação Puntual , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Receptores de Interleucina-1/análise , Receptores de Interleucina-1/genética , Infecções Estafilocócicas/tratamento farmacológico , Ácidos Teicoicos/imunologia , Receptor 2 Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
2.
Nat Immunol ; 15(12): 1134-42, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25344726

RESUMO

Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Adolescente , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Lactente , Quinases Associadas a Receptores de Interleucina-1/imunologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Doenças da Imunodeficiência Primária , Transcriptoma
3.
Nat Immunol ; 13(12): 1178-86, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23104095

RESUMO

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1ß (IL-1ß) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1ß. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1ß responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1ß responses differently in different cell types.


Assuntos
Doença de Depósito de Glicogênio Tipo IV/genética , Doenças Hereditárias Autoinflamatórias/genética , Síndromes de Imunodeficiência/genética , NF-kappa B/metabolismo , Ubiquitina-Proteína Ligases/genética , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Proteínas de Ciclo Celular/genética , Linhagem Celular , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Síndromes de Imunodeficiência/metabolismo , Interleucina-1beta/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Fatores de Transcrição , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
4.
Nat Chem Biol ; 15(3): 304-313, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692685

RESUMO

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies.


Assuntos
Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Regulação da Expressão Gênica , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Linfócitos/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/ultraestrutura , NF-kappa B/metabolismo , Proteínas de Neoplasias , Transdução de Sinais
5.
J Immunol ; 203(11): 2791-2806, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31659015

RESUMO

The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.


Assuntos
Autoimunidade/imunologia , Homeostase/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética
6.
J Pers Assess ; 103(3): 392-405, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32207995

RESUMO

We present two openly accessible databases related to the assessment of implicit motives using Picture Story Exercises (PSEs): (a) A database of 183,415 German sentences, nested in 26,389 stories provided by 4,570 participants, which have been coded by experts using Winter's coding system for the implicit affiliation/intimacy, achievement, and power motives, and (b) a database of 54 classic and new pictures which have been used as PSE stimuli. Updated picture norms are provided which can be used to select appropriate pictures for PSE applications. Based on an analysis of the relations between raw motive scores, word count, and sentence count, we give recommendations on how to control motive scores for story length, and validate the recommendation with a meta-analysis on gender differences in the implicit affiliation motive that replicates existing findings. We discuss to what extent the guiding principles of the story length correction can be generalized to other content coding systems for narrative material. Several potential applications of the databases are discussed, including (un)supervised machine learning of text content, psychometrics, and better reproducibility of PSE research.


Assuntos
Logro , Identificação Psicológica , Relações Interpessoais , Autoimagem , Teste de Apercepção Temática/normas , Adulto , Alemanha , Humanos , Masculino , Motivação , Psicometria , Reprodutibilidade dos Testes , Fatores Sexuais , Inquéritos e Questionários
7.
Behav Res Methods ; 53(2): 574-592, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32761313

RESUMO

The present study explored the interrelations between a broad set of appraisal ratings and five physiological signals, including facial EMG, electrodermal activity, and heart rate variability, that were assessed in 157 participants watching 10 emotionally charged videos. A total of 134 features were extracted from the physiological data, and a benchmark comparing different kinds of machine learning algorithms was conducted to test how well the appraisal dimensions can be predicted from these features. For 13 out of 21 appraisals, a robust positive R2 was attained, indicating that the dimensions are actually related to the considered physiological channels. The highest R2 (.407) was reached for the appraisal dimension intrinsic pleasantness. Moreover, the comparison of linear and nonlinear algorithms and the inspection of the links between the appraisals and single physiological features using accumulated local effects plots indicates that the relationship between physiology and appraisals is nonlinear. By constructing different importance measures for the assessed physiological channels, we showed that for the 13 predictable appraisals, the five channels explained different amounts of variance and that only a few blocks incrementally explained variance beyond the other physiological channels.


Assuntos
Emoções , Expressão Facial , Atenção , Face , Humanos , Aprendizado de Máquina
8.
Proc Natl Acad Sci U S A ; 114(4): E514-E523, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28069966

RESUMO

Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1ß. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1ß. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.


Assuntos
Fibroblastos/metabolismo , Quinases Associadas a Receptores de Interleucina-1/deficiência , Receptores Toll-Like/metabolismo , Deleção Cromossômica , Cromossomos Humanos X/genética , Humanos , Lactente , Quinases Associadas a Receptores de Interleucina-1/genética , Leucócitos/metabolismo , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Receptores Toll-Like/genética
9.
Blood ; 120(25): 4992-5001, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23002119

RESUMO

We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor-associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM(+)IgD(+)CD27(+) B cells were not affected in these patients. In contrast, the numbers of IgM(+)IgD(+)CD27(+) B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B-dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM(+)IgD(+)CD27(+) compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM(+)IgD(+)CD27(+) B cells in humans.


Assuntos
Linfócitos B/imunologia , Imunoglobulina D/imunologia , Imunoglobulina M/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Citocinas/imunologia , Humanos , Imunoglobulina D/análise , Imunoglobulina M/análise , Mutação , Receptor 10 Toll-Like/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise , Adulto Jovem
10.
Blood ; 118(4): 926-35, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21622647

RESUMO

Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID-causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID-causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding-dependent receptors, the TNF and IL-1ß receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-κB activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/genética , Ubiquitina/metabolismo , Western Blotting , Displasia Ectodérmica Anidrótica Tipo 1/metabolismo , Ativação Enzimática/genética , Feminino , Humanos , Quinase I-kappa B/metabolismo , Síndromes de Imunodeficiência/metabolismo , Masculino , Mutação de Sentido Incorreto , NF-kappa B/metabolismo , Linhagem , Ligação Proteica , Dobramento de Proteína , Transdução de Sinais/genética , Adulto Jovem
11.
Oncogenesis ; 10(4): 32, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824280

RESUMO

CARD-CC complexes involving BCL10 and MALT1 are major cellular signaling hubs. They govern NF-κB activation through their scaffolding properties as well as MALT1 paracaspase function, which cleaves substrates involved in NF-κB regulation. In human lymphocytes, gain-of-function defects in this pathway lead to lymphoproliferative disorders. CARD10, the prototypical CARD-CC protein in non-hematopoietic cells, is overexpressed in several cancers and has been associated with poor prognosis. However, regulation of CARD10 remains poorly understood. Here, we identified CARD10 as the first MALT1 substrate in non-hematopoietic cells and showed that CARD10 cleavage by MALT1 at R587 dampens its capacity to activate NF-κB. Preventing CARD10 cleavage in the lung tumor A549 cell line increased basal levels of IL-6 and extracellular matrix components in vitro, and led to increased tumor growth in a mouse xenograft model, suggesting that CARD10 cleavage by MALT1 might be a built-in mechanism controlling tumorigenicity.

12.
Arthritis Rheumatol ; 72(6): 919-930, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31943941

RESUMO

OBJECTIVE: Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain-containing protein 9, B cell CLL/lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) is required for optimal FcγR-induced canonical NF-κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT-1 protease activity in FcγR-driven events and evaluate the therapeutic potential of selective MALT-1 protease inhibitors in FcγR-mediated diseases. METHODS: Using genetic and pharmacologic disruption of MALT-1 scaffolding and enzymatic activity, we assessed the relevance of MALT-1 function in murine and human primary myeloid cells upon stimulation with immune complexes (ICs) and in murine models of autoantibody-driven arthritis and immune thrombocytopenic purpura (ITP). RESULTS: MALT-1 protease function is essential for optimal FcγR-induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with ICs. In contrast, MALT-1 protease inhibition did not affect the Syk-dependent, FcγR-mediated production of reactive oxygen species or leukotriene B4 . Notably, pharmacologic MALT-1 protease inhibition in vivo reduced joint inflammation in the murine K/BxN serum-induced arthritis model (mean area under the curve for paw swelling of 45.42% versus 100% in control mice; P = 0.0007) but did not affect platelet depletion in a passive model of ITP. CONCLUSION: Our findings indicate a specific contribution of MALT-1 protease activity to FcγR-mediated events and suggest that MALT-1 protease inhibitors have therapeutic potential in a subset of FcγR-driven inflammatory disorders.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Receptores de IgG/imunologia , Animais , Complexo Antígeno-Anticorpo/metabolismo , Plaquetas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Células Mieloides/metabolismo
13.
Front Immunol ; 9: 2239, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386326

RESUMO

The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Heterogeneidade Genética , Guanilato Ciclase/imunologia , Proteínas de Membrana/imunologia , Mutação , Psoríase/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B/genética , Proteína 10 de Linfoma CCL de Células B/imunologia , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Psoríase/genética , Psoríase/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
14.
PLoS One ; 12(1): e0169026, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28052131

RESUMO

The paracaspase MALT1 has arginine-directed proteolytic activity triggered by engagement of immune receptors. Recruitment of MALT1 into activation complexes is required for MALT1 proteolytic function. Here, co-expression of MALT1 in HEK293 cells, either with activated CARD11 and BCL10 or with TRAF6, was used to explore the mechanism of MALT1 activation at the molecular level. This work identified a prominent self-cleavage site of MALT1 isoform A (MALT1A) at R781 (R770 in MALT1B) and revealed that TRAF6 can activate MALT1 independently of the CBM. Intramolecular cleavage at R781/R770 removes a C-terminal TRAF6-binding site in both MALT1 isoforms, leaving MALT1B devoid of the two key interaction sites with TRAF6. A previously identified auto-proteolysis site of MALT1 at R149 leads to deletion of the death-domain, thereby abolishing interaction with BCL10. By using MALT1 isoforms and cleaved fragments thereof, as well as TRAF6 WT and mutant forms, this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover. The MALT1 fragment generated by N-terminal self-cleavage at R149 was labile and displayed enhanced signaling properties that required an intact K644 residue, previously shown to be a site for mono-ubiquitination of MALT1. Conversely, C-terminal self-cleavage at R781/R770 hampered the ability for self-cleavage at R149 and stabilized MALT1 by hindering interaction with TRAF6. C-terminal self-cleavage had limited impact on MALT1A but severely reduced MALT1B proteolytic and signaling functions. It also abrogated NF-κB activation by N-terminally cleaved MALT1A. Altogether, this study provides further insights into mechanisms that regulate the scaffolding and activation cycle of MALT1. It also emphasizes the reduced functional capacity of MALT1B as compared to MALT1A.


Assuntos
Caspases/metabolismo , Proteínas de Neoplasias/metabolismo , Isoformas de Proteínas/metabolismo , Linfócitos T/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína 10 de Linfoma CCL de Células B , Western Blotting , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspases/genética , Linhagem Celular , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Células HEK293 , Humanos , Immunoblotting , Células Jurkat , Linfócitos/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Mutagênese , Proteínas de Neoplasias/genética , Isoformas de Proteínas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fator 6 Associado a Receptor de TNF/genética , Ubiquitinação/genética , Ubiquitinação/fisiologia
17.
Science ; 332(6025): 65-8, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21350122

RESUMO

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.


Assuntos
Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/imunologia , Candida albicans , Criança , Pré-Escolar , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Receptores de Interleucina-17/genética , Transdução de Sinais/genética , Células Th17/imunologia
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