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1.
J Virol ; 83(14): 7252-60, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19403670

RESUMO

Diverse members of the Paramyxovirus family of negative-strand RNA viruses effectively suppress host innate immune responses through the actions of their V proteins. The V protein mediates interference with the interferon regulatory RNA helicase MDA5 to avoid cellular antiviral responses. Analysis of the interaction interface revealed the MDA5 helicase C domain as necessary and sufficient for association with V proteins from human parainfluenza virus type 2, parainfluenza virus type 5, measles virus, mumps virus, Hendra virus, and Nipah virus. The identified approximately 130-residue region is highly homologous between MDA5 and the related antiviral helicase LGP2, but not RIG-I. Results indicate that the paramyxovirus V proteins can also associate with LGP2. The V protein interaction was found to disrupt ATP hydrolysis mediated by both MDA5 and LGP2. These findings provide a potential mechanistic basis for V protein-mediated helicase interference and identify LGP2 as a second cellular RNA helicase targeted by paramyxovirus V proteins.


Assuntos
RNA Helicases DEAD-box/metabolismo , Infecções por Paramyxoviridae/metabolismo , Paramyxovirinae/fisiologia , RNA Helicases/metabolismo , Interferência Viral , Trifosfato de Adenosina/metabolismo , Antivirais , Linhagem Celular , RNA Helicases DEAD-box/química , Humanos , Helicase IFIH1 Induzida por Interferon , Infecções por Paramyxoviridae/genética , Infecções por Paramyxoviridae/virologia , Paramyxovirinae/genética , Ligação Proteica , Estrutura Terciária de Proteína , RNA Helicases/química , RNA Helicases/genética , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
2.
J Biol Chem ; 284(15): 9700-12, 2009 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-19211564

RESUMO

Intracellular pattern recognition receptors MDA5, RIG-I, and LGP2 are essential components of the cellular response to virus infection and are homologous to the DEXH box subfamily of RNA helicases. However, the relevance of helicase activity in the regulation of interferon production remains elusive. To examine the importance of the helicase domain function for these signaling proteins, a series of mutations targeting conserved helicase sequence motifs were analyzed for enzymatic activity, RNA binding, interferon induction, and antiviral signaling. Results indicate that all targeted motifs are required for ATP hydrolysis, but a subset is involved in RNA binding. The enzymatically inactive mutants differed in their signaling ability. Notably, mutations to MDA5 motifs I, III, and VI and RIG-I motif III produced helicase proteins with constitutive antiviral activity, whereas mutations in RIG-I motif V retained ATP hydrolysis but failed to mediate signal transduction. These findings demonstrate that type I interferon production mediated by full-length MDA5 and RIG-I is independent of the helicase domain catalytic activity. In addition, neither enzymatic activity nor RNA binding was required for negative regulation of antiviral signaling by LGP2, supporting an RNA-independent interference mechanism.


Assuntos
RNA Helicases DEAD-box/metabolismo , RNA Helicases/metabolismo , Trifosfato de Adenosina/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Antivirais/farmacologia , Proteína DEAD-box 58 , Humanos , Insetos , Helicase IFIH1 Induzida por Interferon , Dados de Sequência Molecular , Ligação Proteica , Receptores Imunológicos , Homologia de Sequência de Aminoácidos , Transdução de Sinais
3.
Cytokine ; 43(3): 350-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18703349

RESUMO

The recent, rapid progress in our understanding of cytoplasmic RNA-mediated antiviral innate immune signaling was initiated by the discovery of retinoic acid-inducible gene I (RIG-I) as a sensor of viral RNA. It is now widely recognized that RIG-I and related RNA helicases, melanoma differentiation-associated gene-5 (MDA5) and laboratory of genetics and physiology-2 (LGP2), can initiate and/or regulate RNA and virus-mediated type I IFN production and antiviral responses. As with other cytokine systems, production of type I IFN is a transient process, and can be hazardous to the host if unregulated, resulting in chronic cellular toxicity or inflammatory and autoimmune diseases. In addition, the RIG-I-like receptor (RLR) system is a fundamental target for virus-encoded immune suppression, with many indirect and direct examples of interference described. In this article, we review the current understanding of endogenous negative regulation in RLR signaling and explore direct inhibition of RLR signaling by viruses as a host immune evasion strategy.


Assuntos
RNA Helicases DEAD-box/fisiologia , Imunidade Inata/fisiologia , Interferon Tipo I/biossíntese , RNA Viral/análise , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína 12 Relacionada à Autofagia , Proteína 5 Relacionada à Autofagia , Citocinas/fisiologia , Proteína DEAD-box 58 , Proteínas de Ligação a DNA , Enzima Desubiquitinante CYLD , Endopeptidases/fisiologia , Humanos , Helicase IFIH1 Induzida por Interferon , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Associadas aos Microtúbulos , Proteínas Mitocondriais/fisiologia , Peptidilprolil Isomerase de Interação com NIMA , Proteínas Nucleares/fisiologia , Correpressor 1 de Receptor Nuclear , Peptidilprolil Isomerase/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , RNA Helicases/fisiologia , Proteínas Repressoras/fisiologia , Transdução de Sinais/fisiologia , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/fisiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Proteínas Supressoras de Tumor/fisiologia , Ubiquitinas/fisiologia
4.
Peptides ; 28(2): 226-34, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17207557

RESUMO

Non-invasive methods for studying biological processes in living cells have become very important, also in the field of GPCR biochemistry. Great advancements in the application of fluorescence techniques as well as in the development and improvement of novel fluorophores allow the visualization of dynamic processes. Using these technologies, problems concerning receptor biosynthesis, internalization, recycling and degradation can be investigated. Here we compare the application of the different fluorescent tags EYFP, Lumiotrade mark and SNAPtrade mark to track hY(1) and hY(5) receptors in living cells.


Assuntos
Receptores de Neuropeptídeo Y/metabolismo , Sequência de Bases , Primers do DNA , Humanos , Microscopia de Fluorescência , Transdução de Sinais
5.
Diabetes ; 55(1): 19-26, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16380472

RESUMO

Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression.


Assuntos
Gorduras na Dieta/farmacologia , Obesidade/genética , Obesidade/prevenção & controle , Receptores de Neuropeptídeo Y/deficiência , Receptores de Neuropeptídeo Y/metabolismo , Animais , Dieta , Comportamento Alimentar , Regulação da Expressão Gênica , Intolerância à Glucose , Hipotálamo/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/anatomia & histologia , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Knockout , Atividade Motora , Receptores de Neuropeptídeo Y/genética , Termogênese
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