RESUMO
In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.
Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Doença Crônica , Humanos , Imunidade , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Fenótipo , Ligação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Transcrição Gênica , Carga ViralRESUMO
In the presence of galactose, lithium ions activate the unfolded protein response (UPR) by inhibiting phosphoglucomutase activity and causing the accumulation of galactose-related metabolites, including galactose-1-phosphate. These metabolites also accumulate in humans who have the disease classic galactosemia. Here, we demonstrate that Saccharomyces cerevisiae yeast strains harboring a deletion of UBX4, a gene encoding a partner of Cdc48p in the endoplasmic reticulum-associated degradation (ERAD) pathway, exhibit delayed UPR activation after lithium and galactose exposure because the deletion decreases galactose-1-phosphate levels. The delay in UPR activation did not occur in yeast strains in which key ERAD or proteasomal pathway genes had been disrupted, indicating that the ubx4Δ phenotype is ERAD-independent. We also observed that the ubx4Δ strain displays decreased oxygen consumption. The inhibition of mitochondrial respiration was sufficient to diminish galactose-1-phosphate levels and, consequently, affects UPR activation. Finally, we show that the deletion of the AMP-activated protein kinase ortholog-encoding gene SNF1 can restore the oxygen consumption rate in ubx4Δ strain, thereby reestablishing galactose metabolism, UPR activation, and cellular adaption to lithium-galactose challenge. Our results indicate a role for Ubx4p in yeast mitochondrial function and highlight that mitochondrial and endoplasmic reticulum functions are intertwined through galactose metabolism. These findings also shed new light on the mechanisms of lithium action and on the pathophysiology of galactosemia.
Assuntos
Galactose/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lítio/farmacologia , Mitocôndrias/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Retículo Endoplasmático/metabolismo , Galactose/metabolismo , Galactosefosfatos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Consumo de Oxigênio , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Splicing de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
SALL2 is a poorly characterized transcription factor that belongs to the Spalt-like family involved in development. Mutations on SALL2 have been associated with ocular coloboma and cancer. In cancers, SALL2 is deregulated and is proposed as a tumor suppressor in ovarian cancer. SALL2 has been implicated in stemness, cell death, proliferation, and quiescence. However, mechanisms underlying roles of SALL2 related to cancer remain largely unknown. Here, we investigated the role of SALL2 in cell proliferation using mouse embryo fibroblasts (MEFs) derived from Sall2-/- mice. Compared to Sall2+/+ MEFs, Sall2-/- MEFs exhibit enhanced cell proliferation and faster postmitotic progression through G1 and S phases. Accordingly, Sall2-/- MEFs exhibit higher mRNA and protein levels of cyclins D1 and E1. Chromatin immunoprecipitation and promoter reporter assays showed that SALL2 binds and represses CCND1 and CCNE1 promoters, identifying a novel mechanism by which SALL2 may control cell cycle. In addition, the analysis of tissues from Sall2+/+ and Sall2-/- mice confirmed the inverse correlation between expression of SALL2 and G1-S cyclins. Consistent with an antiproliferative function of SALL2, immortalized Sall2-/- MEFs showed enhanced growth rate, foci formation, and anchorage-independent growth, confirming tumor suppressor properties for SALL2. Finally, cancer data analyses show negative correlations between SALL2 and G1-S cyclins' mRNA levels in several cancers. Altogether, our results demonstrated that SALL2 is a negative regulator of cell proliferation, an effect mediated in part by repression of G1-S cyclins' expression. Our results have implications for the understanding and significance of SALL2 role under physiological and pathological conditions.
Assuntos
Ciclo Celular/genética , Ciclina D1/genética , Ciclina E/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/genética , Neoplasias/patologia , Proteínas Repressoras/metabolismo , Animais , Proliferação de Células , Transformação Celular Neoplásica/patologia , Ciclina D1/metabolismo , Ciclina E/metabolismo , Proteínas de Ligação a DNA , Fibroblastos/metabolismo , Fase G1 , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Camundongos Knockout , Modelos Biológicos , Fenótipo , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase S , Fatores de Transcrição , Transcrição GênicaAssuntos
Deleção Cromossômica , Cromossomos Humanos Par 21/química , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Proteína-Arginina N-Metiltransferases/genética , Adulto , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Cariotipagem , Fenótipo , Proteínas Serina-Treonina Quinases/deficiência , Proteína-Arginina N-Metiltransferases/deficiênciaAssuntos
Animais , Camundongos , Autoimunidade , Linfócitos B/citologia , Linfócitos B/imunologia , Cisteína Endopeptidases/imunologia , Cisteína Endopeptidases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , /imunologia , /metabolismo , Linfócitos B/enzimologia , Linhagem da Célula , Sobrevivência Celular , Cisteína Endopeptidases/deficiência , Homeostase , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de SinaisRESUMO
We describe 2 siblings who had interleukin-1 receptor-associated kinase 4 deficiency with a novel mutation in exon 2. They had delayed separation of the umbilical cord. The flow cytometric analysis of monocytic intracellular tumor necrosis factor-alpha production in response to lipopolysaccharide may be a useful method to screen for the disease.
Assuntos
Citometria de Fluxo , Síndromes de Imunodeficiência/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Proteínas Serina-Treonina Quinases/deficiência , Fator de Necrose Tumoral alfa/metabolismo , Cordão Umbilical , Biomarcadores/metabolismo , Estudos de Casos e Controles , Pré-Escolar , Éxons/genética , Homozigoto , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Quinases Associadas a Receptores de Interleucina-1 , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos , Masculino , Análise por Pareamento , Monócitos/metabolismo , Mutação , Proteínas Serina-Treonina Quinases/genética , Ácidos TeicoicosRESUMO
We report a kindred with autosomal recessive interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.