Retraction: "CITRX thioredoxin interacts with the tomato Cf-9 resistance protein and negatively regulates defence"
(Source: EMBO Journal)
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Rivas, S., Rougon-Cardoso, A., Smoker, M., Schauser, L., Yoshioka, H., Jones, J. D. Tags: Retraction Source Type: research
Autophagy: clocking in for the night shift
Daily rhythms of biological activity, such as cycles of sleep–wake and feeding–fasting, are coupled to cell-autonomous circadian clocks to synchronize organismal food intake with cellular bioenergetics. Food intake during wake stimulates biosynthesis followed by rest periods of autophagy, which degrades damaged macromolecules and recycles them as nutrients to enhance fitness. In this issue of The EMBO Journal, Pastore et al discovered that regulators of autophagy, TFEB and TFE3, are activated during the rest phase and ultimately drive the expression of Rev-erbα, a component of the core circadian mole...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Brooks, R. C., Dang, C. V. Tags: Autophagy & Cell Death, Metabolism, Molecular Biology of Disease News [amp ] Views Source Type: research
BASC-ing in the glow: bronchioalveolar stem cells get their place in the lung
Lung epithelial progenitor cell populations fulfill the needs of this complex facultative regenerative organ when exposed to insult and contribute to repair in either the airway or alveolar compartments. The presence of a cell that can populate both epithelia had been proposed previously but has remained elusive. In this issue, Salwig et al (2019) provide compelling, genetic evidence that supports a growing narrative—a rare population of bronchioalveolar stem cells (BASCs) that can contribute to both airway and alveolar epithelium in the distal murine lung. (Source: EMBO Journal)
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Basil, M. C., Morrisey, E. E. Tags: Development & Differentiation, Immunology, Stem Cells News [amp ] Views Source Type: research
Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo
Bronchioalveolar stem cells (BASCs) are a potential source for lung regeneration, but direct in vivo evidence for a multipotential lineage contribution during homeostasis and disease is critically missing, since specific genetic labeling of BASCs has not been possible. We developed a novel cell tracing approach based on intein-mediated assembly of newly engineered split-effectors, allowing selective targeting of dual-marker expressing BASCs in the mouse lung. RNA sequencing of isolated BASCs demonstrates that BASCs show a distinct transcriptional profile, characterized by co-expression of bronchiolar and alveolar epit...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Salwig, I., Spitznagel, B., Vazquez-Armendariz, A. I., Khalooghi, K., Guenther, S., Herold, S., Szibor, M., Braun, T. Tags: Development & Differentiation, Immunology, Stem Cells Articles Source Type: research
Extracellular interface between APP and Nicastrin regulates A{beta} length and response to {gamma}-secretase modulators
-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD. GSECs successively cut APP to generate amyloid-β (Aβ) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/Aβn interactions and thus enhance the production of longer Aβs, which elicit neurotoxic ev...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Petit, D., Hitzenberger, M., Lismont, S., Zoltowska, K. M., Ryan, N. S., Mercken, M., Bischoff, F., Zacharias, M., Chavez-Gutierrez, L. Tags: Molecular Biology of Disease, Neuroscience, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly of Ca2+ signaling complexes at the ER/PM compartment
Communication and material transfer between membranes and organelles take place at membrane contact sites (MCSs). MCSs between the ER and PM, the ER/PM junctions, are the sites where the ER Ca2+ sensor STIM1 and the PM Ca2+ influx channel Orai1 cluster. MCSs are formed by tether proteins that bridge the opposing membranes, but the identity and role of these tethers in receptor-evoked Ca2+ signaling is not well understood. Here, we identified Anoctamin 8 (ANO8) as a key tether in the formation of the ER/PM junctions that is essential for STIM1-STIM1 interaction and STIM1-Orai1 interaction and channel activation at a ER/PM P...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Jha, A., Chung, W. Y., Vachel, L., Maleth, J., Lake, S., Zhang, G., Ahuja, M., Muallem, S. Tags: Membrane & Intracellular Transport, Signal Transduction Articles Source Type: research
Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock
Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient-sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24-h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the ...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Pastore, N., Vainshtein, A., Herz, N. J., Huynh, T., Brunetti, L., Klisch, T. J., Mutarelli, M., Annunziata, P., Kinouchi, K., Brunetti-Pierri, N., Sassone-Corsi, P., Ballabio, A. Tags: Autophagy & Cell Death, Metabolism, Transcription Articles Source Type: research
Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells
Several autoimmune diseases including multiple sclerosis (MS) cause increased transcription of endogenous retroviruses (HERVs) normally repressed by heterochromatin. In parallel, HERV-derived sequences were reported to drive gene expression. Here, we have examined a possible link between promoter and enhancer divergent transcription and the production of HERV transcripts. We find that HERV-derived sequences are in general counter-selected at regulatory regions, a counter-selection that is strongest in brain tissues while very moderate in stem cells. By exposing T cells to the pesticide dieldrin, we further found that a ser...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Azebi, S., Batsche, E., Michel, F., Kornobis, E., Muchardt, C. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Molecular Biology of Disease Articles Source Type: research
Epigenetic aberrations in human pluripotent stem cells
Human pluripotent stem cells (hPSCs) are being increasingly utilized worldwide in investigating human development, and modeling and discovering therapies for a wide range of diseases as well as a source for cellular therapy. Yet, since the first isolation of human embryonic stem cells (hESCs) 20 years ago, followed by the successful reprogramming of human-induced pluripotent stem cells (hiPSCs) 10 years later, various studies shed light on abnormalities that sometimes accumulate in these cells in vitro. Whereas genetic aberrations are well documented, epigenetic alterations are not as thoroughly discussed. I...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Bar, S., Benvenisty, N. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Stem Cells Review Source Type: research
3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids
Immunotherapy using chimeric antigen receptor (CAR)-engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR-mediated cytotoxicity in a tissue-like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3-dimensional (3D) patient-derived colon organoids. Luciferase-based measurement served as a quantitative read-out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organ...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Schnalzger, T. E., de Groot, M. H., Zhang, C., Mosa, M. H., Michels, B. E., Röder, J., Darvishi, T., Wels, W. S., Farin, H. F. Tags: Cancer, Immunology, Methods & Resources Source Type: research
Live-cell imaging reveals the interplay between transcription factors, nucleosomes, and bursting
Transcription factors show rapid and reversible binding to chromatin in living cells, and transcription occurs in sporadic bursts, but how these phenomena are related is unknown. Using a combination of in vitro and in vivo single-molecule imaging approaches, we directly correlated binding of the Gal4 transcription factor with the transcriptional bursting kinetics of the Gal4 target genes GAL3 and GAL10 in living yeast cells. We find that Gal4 dwell time sets the transcriptional burst size. Gal4 dwell time depends on the affinity of the binding site and is reduced by orders of magnitude by nucleosomes. Using a nov...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Donovan, B. T., Huynh, A., Ball, D. A., Patel, H. P., Poirier, M. G., Larson, D. R., Ferguson, M. L., Lenstra, T. L. Tags: Transcription Articles Source Type: research
The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment
Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found as multiple paralogous proteins in vertebrate complexes. In some cases, these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here, we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (NuRD) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are ...
Source: EMBO Journal - June 16, 2019 Category: Molecular Biology Authors: Burgold, T., Barber, M., Kloet, S., Cramard, J., Gharbi, S., Floyd, R., Kinoshita, M., Ralser, M., Vermeulen, M., Reynolds, N., Dietmann, S., Hendrich, B. Tags: Development & Differentiation, Stem Cells, Transcription Articles Source Type: research
Mitochondria and pathogen immunity: from killer to firestarter
Serving as an innate defence mechanism, invading pathogens elicit a broad inflammatory response in cells. In this issue, Brokatzky et al (2019) report that pathogens can cause activation of BAX/BAK which permeabilises a limited number of mitochondria. Induction of DNA damage, or release of mtDNA, triggers STING-dependent pro-inflammatory cytokine expression and secretion, revealing an unexpected role for the mitochondrial apoptotic machinery in immune defence. (Source: EMBO Journal)
Source: EMBO Journal - June 2, 2019 Category: Molecular Biology Authors: Riley, J. S., Tait, S. W. Tags: Autophagy & Cell Death, Microbiology, Virology & Host Pathogen Interaction News [amp ] Views Source Type: research
Phospho-RNA-seq: a modified small RNA-seq method that reveals circulating mRNA and lncRNA fragments as potential biomarkers in human plasma
We report that plasma contains fragmented mRNAs and lncRNAs that are missed by standard small RNA-seq protocols due to lack of 5' phosphate or presence of 3' phosphate. These fragments were revealed using a modified protocol ("phospho-RNA-seq") incorporating RNA treatment with T4-polynucleotide kinase, which we compared with standard small RNA-seq for sequencing synthetic RNAs with varied 5' and 3' ends, as well as human plasma exRNA. Analyzing phospho-RNA-seq data using a custom, high-stringency bioinformatic pipeline, we identified mRNA/lncRNA transcriptome fingerprints in plasma, including tissue-specific gene sets. In ...
Source: EMBO Journal - June 2, 2019 Category: Molecular Biology Authors: Giraldez, M. D., Spengler, R. M., Etheridge, A., Goicochea, A. J., Tuck, M., Choi, S. W., Galas, D. J., Tewari, M. Tags: RNA Biology Resource Source Type: research
A non-death function of the mitochondrial apoptosis apparatus in immunity
Apoptosis is a frequent form of programmed cell death, but the apoptotic signaling pathway can also be engaged at a low level, in the absence of cell death. We here report that such sub-lethal engagement of mitochondrial apoptosis signaling causes the secretion of cytokines from human epithelial cells in a process controlled by the Bcl-2 family of proteins. We further show that sub-lethal signaling of the mitochondrial apoptosis pathway is initiated by infections with all tested viral, bacterial, and protozoan pathogens and causes damage to the genomic DNA. Epithelial cells infected with these pathogens secreted cytokines,...
Source: EMBO Journal - June 2, 2019 Category: Molecular Biology Authors: Brokatzky, D., Dörflinger, B., Haimovici, A., Weber, A., Kirschnek, S., Vier, J., Metz, A., Henschel, J., Steinfeldt, T., Gentle, I. E., Häcker, G. Tags: Autophagy & Cell Death, Immunology Articles Source Type: research
