Search

Neonatal diabetes is caused by single gene mutations reducing pancreatic [beta] cell number or impairing [beta] cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in [beta] cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human [beta] cell models (YIPF5 silencing in EndoC-[beta]H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects [beta] cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and p cell failure. Partial YIPF5 silencing in EndoC-[beta]H1 cells and a patient mutation in stem cells increased the [beta] cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in [beta] cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes., Introduction Neonatal diabetes mellitus develops before 6 months of age and is caused by reduced pancreatic [beta] cell number (reduced formation/increased destruction) or impaired [beta] cell function. Previous studies have [...]

Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids (1). The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation (2). Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses (3). However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined (4). Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity., To explore the cellular responses to mtDNA stress in the absence of oxidative phosphorylation deficiency, we employed a TFAM heterozygous knockout ([Tfam.sup.+/-]) mouse model. Cells and tissues from these animals [...]

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation (1). A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia (2, 3). However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a nonfunctional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients., To interrogate whether DNA damage could be induced in vivo by physiological activation of HSCs out of quiescence, we injected C57BL/6J mice with polyinosinic:polycytidylic acid (pI: pC) to mimic a [...]

MicroRNA (miRNA) mediated changes in gene expression by post-transcriptional modulation of major regulatory transcription factors is a potent mechanism for integrating growth and stress-related responses. Exotic plants including many traditional varieties of Andean potatoes (Solanum tuberosum subsp. andigena) are known for better adaptation to marginal environments. Stress physiological studies confirmed earlier reports on the salinity tolerance potentials of certain andigena cultivars. Guided by the hypothesis that certain miRNAs play important roles in growth modulation under suboptimal conditions, we identified and characterized salinity stress-responsive miRNA-target gene pairs in the andigena cultivar Sullu by parallel analysis of noncoding and coding RNA transcriptomes. Inverse relationships were established by the reverse coexpression between two salinity stress-regulated miRNAs (miR166, miR159) and their target transcriptional regulators HD-ZIPPhabulosa/Phavulota and Myb101, respectively. Based on heterologous models in Arabidopsis, the miR166-HD-ZIP-Phabulosa/Phavulota network appears to be involved in modulating growth perhaps by mediating vegetative dormancy, with linkages to defense-related pathways. The miR159-Myb101 network may be important for the modulation of vegetative growth while also controlling stress-induced premature transition to reproductive phase. We postulate that the induction of miR166 and miR159 under salinity stress represents important network hubs for balancing gene expression required for basal growth adjustments. Key words: microRNA, post-transcriptional silencing, regulatory network, dormancy, defenses, Andean potato. Les changements post-transcriptionnels dans l'expression genique d'importants facteurs de transcription, lesquels sont induits par des microARN (miARN), representent un puissant mecanisme pour integrer les signaux en reponse a la croissance et aux stress. Les plantes exotiques incluant plusieurs varietes traditionnelles de pommes de terre andigena (Solanum tuberosum subsp. andigena) sont reconnues presenter une meilleure adaptation aux environnements marginaux. Des etudes sur les stress physiologiques ont confirme des etudes anterieures sur la tolerance au stress salin chez certains cultivars andigena. Guides par l'hypothese que certains miARN jouent des roles importants dans la modulation de la croissance en conditions suboptimales, les auteurs ont identifie et caracterise des paires miARN-gene cible modulees par le stress salin chez le cultivar andigena Sullu par analyse parallele des transcriptomes codant et non-codant. Des relations inverses ont ete etablies entre l'expression de deux miARN regules par le stress salin (miR166, miR159) et les regulateurs transcriptionnels qu'ils controlent (HD-ZIP-Phabulosa/Phavoluta et Myb101, respectivement). Sur la base des modeles heterologues chez Arabidopsis, le reseau miR166HD-ZIP-Phabulosa/Phavoluta semblerait implique dans la modulation de la croissance, possiblement en affectant la dormance vegetative, tout en ayant des liens avec les sentiers de defense. Le reseau miR159-Myb101 serait possiblement implique dans la modulation de la croissance vegetative tout en determinant une transition prematuree a la phase reproductive induite par le stress. Les auteurs proposent que l'induction de miR166 et miR159 en conditions de stress salin met en place d'importants points de controle pour equilibrer l'expression genique, des ajustements requis au programme de croissance. [Traduit par la Redaction] Mots-cles: microARN, inhibition post-transcriptionnelle, reseau de controle, dormance, defenses, pomme de terre andigena., Introduction The modern cultivars of tetraploid potato (Solanum tuberosum subsp. tuberosum) have been selected and bred for adaptation to mild temperate agricultural environments, thus they represent relatively limited genetic variation [...]