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1.
PLoS Pathog ; 13(2): e1006232, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28235043

RESUMO

Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3' UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence.


Assuntos
Hepatite C/imunologia , Evasão da Resposta Imune/imunologia , Ativação Linfocitária/imunologia , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/imunologia , Linfócitos T/imunologia , Ensaio de Imunoadsorção Enzimática , Hepacivirus/imunologia , Humanos , Immunoblotting , RNA Viral/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transfecção
2.
J Immunol ; 185(10): 5993-6002, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20944008

RESUMO

Mast cell activation via FcεRI involves activation of the Src family kinases (SFKs) Lyn, Fyn, and Hck that positively or, in the case of Lyn, negatively regulate cellular responses. Little is known of upstream activators of these SFKs in FcεRI-dependent signaling. We investigated the role of receptor protein tyrosine phosphatase (PTP)α, a well-known activator of SFKs in diverse signaling systems, FcεRI-mediated mast cell activation, and IgE-dependent allergic responses in mice. PTPα(-/-) bone marrow-derived mast cells hyperdegranulate and exhibit increased cytokine and cysteinyl leukotriene secretion, and PTPα(-/-) mice display enhanced IgE-dependent anaphylaxis. At or proximal to FcεRI, PTPα(-/-) cells have reduced IgE-dependent activation of Lyn and Fyn, as well as reduced FcεRI and SHIP phosphorylation. In contrast, Hck and Syk activation is enhanced. Syk hyperactivation correlated with its increased phosphorylation at positive regulatory sites and defective phosphorylation at a negative regulatory site. Distal to FcεRI, we observed increased activation of PI3K and MAPK pathways. These findings demonstrate that PTPα activates the FcεRI-coupled kinases Lyn and Fyn and suppresses Hck activity. Furthermore, the findings indicate that hyperactivation of PTPα(-/-) mast cells and enhanced IgE-dependent allergic responses of PTPα(-/-) mice are due to the ablated function of PTPα as a critical regulator of Lyn negative signaling.


Assuntos
Mastócitos/imunologia , Proteínas Proto-Oncogênicas c-fyn/imunologia , Proteínas Proto-Oncogênicas c-hck/imunologia , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/imunologia , Quinases da Família src/imunologia , Animais , Degranulação Celular/imunologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Proteínas Proto-Oncogênicas c-hck/metabolismo , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/metabolismo , Receptores de IgE/imunologia , Receptores de IgE/metabolismo , Transdução de Sinais/imunologia , Quinases da Família src/metabolismo
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