Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction
Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi-omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans. We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Gioran, A., Piazzesi, A., Bertan, F., Schroer, J., Wischhof, L., Nicotera, P., Bano, D. Tags: Membrane & Intracellular Transport, Metabolism, Signal Transduction Articles Source Type: research
A multifaceted small RNA modulates gene expression upon glucose limitation in Staphylococcus aureus
Pathogenic bacteria must rapidly adapt to ever-changing environmental signals resulting in metabolism remodeling. The carbon catabolite repression, mediated by the catabolite control protein A (CcpA), is used to express genes involved in utilization and metabolism of the preferred carbon source. Here, we have identified RsaI as a CcpA-repressed small non-coding RNA that is inhibited by high glucose concentrations. When glucose is consumed, RsaI represses translation initiation of mRNAs encoding a permease of glucose uptake and the FN3K enzyme that protects proteins against damage caused by high glucose concentrations. RsaI...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Bronesky, D., Desgranges, E., Corvaglia, A., Francois, P., Caballero, C. J., Prado, L., Toledo-Arana, A., Lasa, I., Moreau, K., Vandenesch, F., Marzi, S., Romby, P., Caldelari, I. Tags: Metabolism, Microbiology, Virology & Host Pathogen Interaction, RNA Biology Articles Source Type: research
An increase in neural stem cells and olfactory bulb adult neurogenesis improves discrimination of highly similar odorants
Adult neurogenesis is involved in cognitive performance but studies that manipulated this process to improve brain function are scarce. Here, we characterized a genetic mouse model in which neural stem cells (NSC) of the subventricular zone (SVZ) were temporarily expanded by conditional expression of the cell cycle regulators Cdk4/cyclinD1, thus increasing neurogenesis. We found that supernumerary neurons matured and integrated in the olfactory bulb similarly to physiologically generated newborn neurons displaying a correct expression of molecular markers, morphology and electrophysiological activity. Olfactory performance...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Bragado Alonso, S., Reinert, J. K., Marichal, N., Massalini, S., Berninger, B., Kuner, T., Calegari, F. Tags: Neuroscience Articles Source Type: research
Ubiquitin--a beacon for all during quality control on the ribosome
Ribosome stalling triggers no-go decay (NGD) and ribosome-associated quality control (RQC) pathways to rapidly degrade the aberrant mRNA and the incomplete nascent peptide, respectively. Two recent studies in yeast and mammalian systems reveal the importance of stalling-induced ribosomal protein ubiquitination by Hel2/ZNF598 for both NGD and RQC. The studies also structurally explain how collided ribosomes generate a unique interface not present in monosomes, which can be recognized by Hel2/ZNF598 ubiquitin ligases. (Source: EMBO Journal)
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Yan, L. L., Zaher, H. S. Tags: Post-translational Modifications, Proteolysis & Proteomics, Protein Biosynthesis & Quality Control, Structural Biology News [amp ] Views Source Type: research
Length doesn't matter--telomere damage triggers cellular senescence in the ageing heart
Telomere shortening induces cellular senescence in proliferative cells. Yet, it is presently unclear how it is triggered in post-mitotic cells such as cardiac myocytes. A new study by Anderson et al (2019) reports that during ageing of the heart, cellular senescence develops independently of telomere length, but is evoked by DNA damage, which preferentially accumulates at the telomere. Removal of senescent cells using senolytic drugs ameliorated cardiac hypertrophy and fibrosis and may inform novel approaches to improve the conditions for the ageing heart. (Source: EMBO Journal)
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Brand, T. Tags: Ageing, DNA Replication, Repair & Recombination, Metabolism News [amp ] Views Source Type: research
Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange factor Ras GRP1
(Source: EMBO Journal)
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Caloca, M. J., Zugaza, J. L., Matallanas, D., Crespo, P., Bustelo, X. R. Tags: Corrigendum Source Type: research
Abnormal TDP-43 function impairs activity-dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing
Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be r...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Tann, J. Y., Wong, L.-W., Sajikumar, S., Ibanez, C. F. Tags: Molecular Biology of Disease, Neuroscience Articles Source Type: research
The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-{kappa}B signaling and STING's dual role during MCMV infection
Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING-mediated IRF signaling,...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Stempel, M., Chan, B., Juranic Lisnic, V., Krmpotic, A., Hartung, J., Paludan, S. R., Füllbrunn, N., Lemmermann, N. A., Brinkmann, M. M. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Length-independent telomere damage drives post-mitotic cardiomyocyte senescence
Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell divis...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Anderson, R., Lagnado, A., Maggiorani, D., Walaszczyk, A., Dookun, E., Chapman, J., Birch, J., Salmonowicz, H., Ogrodnik, M., Jurk, D., Proctor, C., Correia-Melo, C., Victorelli, S., Fielder, E., Berlinguer-Palmini, R., Owens, A., Greaves, L. C., Kolsky, Tags: Ageing, DNA Replication, Repair & Recombination, Metabolism Articles Source Type: research
Localized incorporation of outer membrane components in the pathogen Brucella abortus
The zoonotic pathogen Brucella abortus is part of the Rhizobiales, which are alpha-proteobacteria displaying unipolar growth. Here, we show that this bacterium exhibits heterogeneity in its outer membrane composition, with clusters of rough lipopolysaccharide co-localizing with the essential outer membrane porin Omp2b, which is proposed to allow facilitated diffusion of solutes through the porin. We also show that the major outer membrane protein Omp25 and peptidoglycan are incorporated at the new pole and the division site, the expected growth sites. Interestingly, lipopolysaccharide is also inserted at the same growth si...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Vassen, V., Valotteau, C., Feuillie, C., Formosa-Dague, C., Dufrene, Y. F., De Bolle, X. Tags: Membrane & Intracellular Transport, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Collided ribosomes form a unique structural interface to induce Hel2-driven quality control pathways
Ribosome stalling triggers quality control pathways targeting the mRNA (NGD: no-go decay) and the nascent polypeptide (RQC: ribosome-associated quality control). RQC requires Hel2-dependent uS10 ubiquitination and the RQT complex in yeast. Here, we report that Hel2-dependent uS10 ubiquitination and Slh1/Rqt2 are crucial for RQC and NGD induction within a di-ribosome (disome) unit, which consists of the leading stalled ribosome and the following colliding ribosome. Hel2 preferentially ubiquitinated a disome over a monosome on a quality control inducing reporter mRNA in an in vitro translation reaction. Cryo-EM analysis...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Ikeuchi, K., Tesina, P., Matsuo, Y., Sugiyama, T., Cheng, J., Saeki, Y., Tanaka, K., Becker, T., Beckmann, R., Inada, T. Tags: Post-translational Modifications, Proteolysis & Proteomics, Protein Biosynthesis & Quality Control, Structural Biology Articles Source Type: research
Endophilin-A regulates presynaptic Ca2+ influx and synaptic vesicle recycling in auditory hair cells
Ribbon synapses of cochlear inner hair cells (IHCs) operate with high rates of neurotransmission; yet, the molecular regulation of synaptic vesicle (SV) recycling at these synapses remains poorly understood. Here, we studied the role of endophilins-A1-3, endocytic adaptors with curvature-sensing and curvature-generating properties, in mouse IHCs. Single-cell RT–PCR indicated the expression of endophilins-A1-3 in IHCs, and immunoblotting confirmed the presence of endophilin-A1 and endophilin-A2 in the cochlea. Patch-clamp recordings from endophilin-A-deficient IHCs revealed a reduction of Ca2+ influx and exocytosis, w...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Kroll, J., Jaime Tobon, L. M., Vogl, C., Neef, J., Kondratiuk, I., König, M., Strenzke, N., Wichmann, C., Milosevic, I., Moser, T. Tags: Neuroscience Articles Source Type: research
Structures of the heart specific SERCA2a Ca2+-ATPase
The sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2–AlF4– form (3.3 Å) and the Ca2+-occluded [Ca2]E1-AMPPCP...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Sitsel, A., De Raeymaecker, J., Drachmann, N. D., Derua, R., Smaardijk, S., Andersen, J. L., Vandecaetsbeek, I., Chen, J., De Maeyer, M., Waelkens, E., Olesen, C., Vangheluwe, P., Nissen, P. Tags: Membrane & Intracellular Transport, Structural Biology Articles Source Type: research
EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis
In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5'UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growt...
Source: EMBO Journal - March 1, 2019 Category: Molecular Biology Authors: Zhao, Y., Ding, L., Wang, D., Ye, Z., He, Y., Ma, L., Zhu, R., Pan, Y., Wu, Q., Pang, K., Hou, X., Weroha, S. J., Han, C., Coleman, R., Coleman, I., Karnes, R. J., Zhang, J., Nelson, P. S., Wang, L., Huang, H. Tags: Cancer, Molecular Biology of Disease, Protein Biosynthesis & Quality Control Articles Source Type: research
An airway organoid is forever
In the last decade, the generation and maintenance of organotypic structures has been propelled to the center stage of biomedical research. In the lung, a variety of protocols has been devised to generate organoids mimicking lung structures, but most methods with human cells have complicated lengthy protocols or a progressive decline in differentiation potential and physiological function with increasing passaging. A new study from Sachs et al (2019) seeks to solve these issues, providing a versatile methodology to efficiently isolate, indefinitely culture, and manipulate human airway organoids, potentially allowing t...
Source: EMBO Journal - February 15, 2019 Category: Molecular Biology Authors: Paschini, M., Kim, C. F. Tags: Development & Differentiation, Methods & Resources, Molecular Biology of Disease News [amp ] Views Source Type: research
