Assuntos
Hispânico ou Latino , Hospitalização , Pênfigo , Índice de Gravidade de Doença , Humanos , Pênfigo/etnologia , Pênfigo/epidemiologia , Pênfigo/diagnóstico , Estudos Retrospectivos , Hispânico ou Latino/estatística & dados numéricos , Feminino , Masculino , Hospitalização/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Idoso , Adulto JovemRESUMO
Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.
Assuntos
Proteínas de Bactérias/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Mimetismo Molecular/imunologia , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Linhagem Celular , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Humanos , Imunidade Inata , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/imunologia , Salmonella , Transdução de SinaisRESUMO
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.