RESUMEN
Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2-/- ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2-/- gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.
Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae , Glucólisis , Proteínas HMGB , Inmunidad Innata , Linfocitos , Ratones Noqueados , Animales , Ratones , Adaptación Fisiológica/inmunología , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , Hexoquinasa/metabolismo , Hexoquinasa/genética , Interleucina-17/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Transactivadores/metabolismo , Transactivadores/genética , Proteínas HMGB/genética , Proteínas HMGB/inmunología , Proteínas HMGB/metabolismoRESUMEN
Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. By using Foxn1-Cre-driven ablation of Klf6 gene in TEC, we identified Klf6 as a critical factor in TEC development. Klf6 deficiency resulted in a hypoplastic thymus-evident from fetal stages into adulthood-in which a dramatic increase in the frequency of apoptotic TEC was observed. Among cortical TEC (cTEC), a previously unreported cTEC population expressing the transcription factor Sox10 was relatively expanded. Within medullary TEC (mTEC), mTEC I and Tuft-like mTEC IV were disproportionately decreased. Klf6 deficiency altered chromatin accessibility and affected TEC chromatin configuration. Consistent with these defects, naïve conventional T cells and invariant natural killer T cells were reduced in the spleen. Late stages of T cell receptor-dependent selection of thymocytes were affected, and mice exhibited autoimmunity. Thus, Klf6 has a prosurvival role and affects the development of specific TEC subsets contributing to thymic function.
Asunto(s)
Regulación de la Expresión Génica , Timocitos , Animales , Ratones , Diferenciación Celular/genética , Cromatina/metabolismo , Células Epiteliales/metabolismo , Ratones Endogámicos C57BL , Timocitos/metabolismo , Timo/metabolismoRESUMEN
The thymus is required for the development of both adaptive and innate-like T cell subsets. There is keen interest in manipulating thymic function for therapeutic purposes in circumstances of autoimmunity, immunodeficiency, and for purposes of immunotherapy. Within the thymus, thymic epithelial cells play essential roles in directing T cell development. Several transcription factors are known to be essential for thymic epithelial cell development and function, and a few transcription factors have been studied in considerable detail. However, the role of many other transcription factors is less well understood. Further, it is likely that roles exist for other transcription factors not yet known to be important in thymic epithelial cells. Recent progress in understanding of thymic epithelial cell heterogeneity has provided some new insight into transcriptional requirements in subtypes of thymic epithelial cells. However, it is unknown whether progenitors of thymic epithelial cells exist in the adult thymus, and consequently, developmental relationships linking putative precursors with differentiated cell types are poorly understood. While we do not presently possess a clear understanding of stage-specific requirements for transcription factors in thymic epithelial cells, new single-cell transcriptomic and epigenomic technologies should enable rapid progress in this field. Here, we review our current knowledge of transcription factors involved in the development, maintenance, and function of thymic epithelial cells, and the mechanisms by which they act.
Asunto(s)
Epigénesis Genética , Células Epiteliales , Diferenciación Celular , Células Epiteliales/fisiología , Humanos , Subgrupos de Linfocitos T/metabolismo , Timo , Factores de Transcripción/genéticaRESUMEN
Accumulating evidence strongly indicates that the presence of cancer stem cells (CSCs) leads to the emergence of worse clinical scenarios, such as chemo- and radiotherapy resistance, metastasis, and cancer recurrence. CSCs are a highly tumorigenic population characterized by self-renewal capacity and differentiation potential. Thus, CSCs establish a hierarchical intratumor organization that enables tumor adaptation to evade the immune response and resist anticancer therapy. YY1 functions as a transcription factor, RNA-binding protein, and 3D chromatin regulator. Thus, YY1 has multiple effects and regulates several molecular processes. Emerging evidence indicates that the development of lethal YY1-mediated cancer phenotypes is associated with the presence of or enrichment in cancer stem-like cells. Therefore, it is necessary to investigate whether and to what extent YY1 regulates the CSC phenotype. Since CSCs mirror the phenotypic behavior of stem cells, we initially describe the roles played by YY1 in embryonic and adult stem cells. Next, we scrutinize evidence supporting the contributions of YY1 in CSCs from a number of various cancer types. Finally, we identify new areas for further investigation into the YY1-CSCs axis, including the participation of YY1 in the CSC niche.
Asunto(s)
Células Madre Neoplásicas , Carcinogénesis/patología , Humanos , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/metabolismo , Factores de Transcripción/metabolismo , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
Abstract: In mammals, apoptosis is the main mechanism to eliminate unwanted cells, securing tissue homeostasis and consequently maintaining the health in the organism. Classically, apoptosis culminates with the activation of caspases, which are enzymes that display cysteine protease activity to degrade specific substrates implied in essential cellular processes. This process is highly regulated. A key regulation mechanism is mediated by the Inhibitor of Apoptosis Proteins (IAPs) family members, which inhibit the activated forms of caspases through physical interaction with them. Smac/DIABLO, a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions, derepresses the IAP-mediated caspase inhibition through physical interaction with IAPs. The first four amino acids (AVPI) of Smac/DIABLO mediate the interaction with IAPs and subsequent apoptosis induction. This interaction has lead to the creation of small molecules mimicking the AVPI segment for potential anticancer therapy. Nevertheless, several studies have pointed out the existence of AVPI-independent functions of Smac/DIABLO. The aim of this review was to provide a landscape of these underestimated AVPI-independent biological functions that have been observed using different approaches, such as the study of endogenous splice variant isoforms and truncated and mutated artificial proteins.
Resumen: La apoptosis es uno de los principales mecanismos en los mamíferos para eliminar células no deseadas, asegurando la homeostasis de los tejidos y, consecuentemente, la salud de los mismos. De forma clásica, la apoptosis finaliza con la activación de las caspasas, enzimas que despliegan actividad de proteasas de cisteína, involucradas en la degradación de sustratos específicos implicados en procesos celulares esenciales. El proceso apoptótico se encuentra altamente regulado. Un mecanismo de regulación es el mediado por los miembros de la familia de las Proteínas Inhibidoras de la Apoptosis (PIA), las cuales inhiben a las formas activas de las caspasas a través de la interacción física con estas. Smac/DIABLO, proteína mitocondrial que es translocada al citoplasma en condiciones apoptóticas, antagoniza la inhibición de las caspasas mediante su interacción física con las PIA. Los cuatro primeros aminoácidos (AVPI) de Smac/DIABLO intervienen en su asociación con las PIA y la subsecuente inducción apoptótica. Esto ha guiado a la generación de pequeñas moléculas miméticas del segmento AVPI para el uso potencial como una terapia anti-cancerígena. Sin embargo, varios estudios han indicado la presencia de funciones en Smac/DIABLO independientes del AVPI. El objetivo de esta revisión fue proporcionar un panorama de estas funciones biológicas desestimadas —independientes al AVPI— las cuales se han observado utilizando diferentes aproximaciones, como el estudio de las isoformas generadas por el procesamiento alternativo del gen y la síntesis de proteínas artificialmente mutadas.
RESUMEN
In mammals, apoptosis is the main mechanism to eliminate unwanted cells, securing tissue homeostasis and consequently maintaining the health in the organism. Classically, apoptosis culminates with the activation of caspases, which are enzymes that display cysteine protease activity to degrade specific substrates implied in essential cellular processes. This process is highly regulated. A key regulation mechanism is mediated by the Inhibitor of Apoptosis Proteins (IAPs) family members, which inhibit the activated forms of caspases through physical interaction with them. Smac/DIABLO, a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions, derepresses the IAP-mediated caspase inhibition through physical interaction with IAPs. The first four amino acids (AVPI) of Smac/DIABLO mediate the interaction with IAPs and subsequent apoptosis induction. This interaction has lead to the creation of small molecules mimicking the AVPI segment for potential anticancer therapy. Nevertheless, several studies have pointed out the existence of AVPI-independent functions of Smac/DIABLO. The aim of this review was to provide a landscape of these underestimated AVPI-independent biological functions that have been observed using different approaches, such as the study of endogenous splice variant isoforms and truncated and mutated artificial proteins.
RESUMEN
XAF1 is a tumour suppressor gene that compromises cell viability by modulating different cellular events such as mitosis, cell cycle progression and apoptosis. In cancer, the XAF1 gene is commonly silenced by CpG-dinucleotide hypermethylation of its promoter. DNA demethylating agents induce transcriptional reactivation of XAF1, sensitizing cancer cells to therapy. The molecular mechanisms that mediate promoter CpG methylation have not been previously studied. Here, we demonstrate that CTCF interacts with the XAF1 promoter in vivo in a methylation-sensitive manner. By transgene assays, we demonstrate that CTCF mediates the open-chromatin configuration of the XAF1 promoter, inhibiting both CpG-dinucleotide methylation and repressive histone posttranslational modifications. In addition, the absence of CTCF in the XAF1 promoter inhibits transcriptional activation induced by well-known apoptosis activators. We report for the first time that epigenetic silencing of the XAF1 gene is a consequence of the loss of CTCF binding.