RESUMO
The transcription factor STAT1 is essential for interferon (IFN)-mediated immunity in humans and mice. STAT1 function is tightly regulated, and both loss- and gain-of-function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1α and STAT1ß, differ with regard to a C-terminal transactivation domain, which is absent in STAT1ß. STAT1ß is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1α. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1α or STAT1ß. As expected, the functions of STAT1α and STAT1ß in IFN-α/ß- and IFN-λ-dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1ß is transcriptionally active in response to IFN-γ. In the absence of STAT1α, STAT1ß shows more prolonged IFN-γ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-γ-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contributions of the individual STAT1 isoforms to STAT1-dependent immune responses. Knowledge of STAT1ß's function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity.
Assuntos
Genes Dominantes , Imunidade Inata/efeitos dos fármacos , Interferon gama/farmacologia , Fator de Transcrição STAT1/metabolismo , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Introdução de Genes , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Interferon beta/farmacologia , Listeria/efeitos dos fármacos , Listeria/fisiologia , Listeriose/imunologia , Listeriose/patologia , Camundongos , Muromegalovirus/efeitos dos fármacos , Muromegalovirus/fisiologia , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico/efeitos dos fármacos , Fator de Transcrição STAT1/deficiência , Transcrição Gênica/efeitos dos fármacosRESUMO
Tyrosine kinase 2 (TYK2) has a pivotal role in immunity to infection and tumor surveillance. It is associated with several cytokine receptor chains including type I interferon (IFN) receptor 1 (IFNAR1), interleukin- (IL-) 12 receptor beta 1 (IL-12Rb1) and IL-10R2. We have generated a mouse with a conditional Tyk2 null allele and proved integrity of the conditional Tyk2 locus. TYK2 was successfully removed by the use of ubiquitous and tissue-specific Cre-expressing mouse strains. Myeloid TYK2 was found to critically contribute to the defense against murine cytomegalovirus. Ubiquitous TYK2 ablation severely impaired tumor immunosurveillance, while deletion in myeloid, dendritic or T cells alone showed no effect. The conditional Tyk2 mouse strain will be instrumental to further dissect TYK2 functions in infection, inflammation and cancer.