The hypothalamic-LC-PFC axis: a new "ace" in the brain for fast-behavioral stress response
>The prefrontal cortex (PFC) is a key site for orchestrating responses to acute stress. In this issue of The EMBO Journal, Alpár et al (2018) unveil a novel pathway converting hypothalamic activation into fast enhancement of cortical excitability following acute stress. The route is initiated by corticotropin-releasing hormone (CRH) hypothalamic neurons, triggering the release of ciliary neurotrophic factor (CNTF) in the brain aqueductal system, which in turns selectively heightens the activity of noradrenergic neurons projecting to the PFC. (Source: EMBO Journal)
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Pozzi, D., Matteoli, M. Tags: Neuroscience News [amp ] Views Source Type: research
Right time, right place--DNA damage and DNA replication checkpoints collectively safeguard S phase
The DNA replication checkpoint (DRC) and the DNA damage checkpoint (DDC) are two closely linked signaling cascades that adjust S phase to the presence of DNA lesions and other replication impediments. Two recent studies published in The EMBO Journal shed new light on their relationship in budding yeast, collectively showing that the two pathways—while sharing several factors—differ in the location and kinetics of their activation, suggesting that they constitute different branches of an integrated cellular response to impaired DNA replication. (Source: EMBO Journal)
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Galanti, L., Pfander, B. Tags: DNA Replication, Repair & Recombination News [amp ] Views Source Type: research
Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic n...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Alpar, A., Zahola, P., Hanics, J., Hevesi, Z., Korchynska, S., Benevento, M., Pifl, C., Zachar, G., Perugini, J., Severi, I., Leitgeb, P., Bakker, J., Miklosi, A. G., Tretiakov, E., Keimpema, E., Arque, G., Tasan, R. O., Sperk, G., Malenczyk, K., Mate, Z. Tags: Neuroscience Articles Source Type: research
Conformational dynamics of the ABC transporter McjD seen by single-molecule FRET
ABC transporters utilize ATP for export processes to provide cellular resistance against toxins, antibiotics, and harmful metabolites in eukaryotes and prokaryotes. Based on static structure snapshots, it is believed that they use an alternating access mechanism, which couples conformational changes to ATP binding (outward-open conformation) and hydrolysis (inward-open) for unidirectional transport driven by ATP. Here, we analyzed the conformational states and dynamics of the antibacterial peptide exporter McjD from Escherichia coli using single-molecule Förster resonance energy transfer (smFRET). For the first tim...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Husada, F., Bountra, K., Tassis, K., de Boer, M., Romano, M., Rebuffat, S., Beis, K., Cordes, T. Tags: Membrane & Intracellular Transport, Structural Biology Articles Source Type: research
ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival
Although lysosomes perform a number of essential cellular functions, damaged lysosomes represent a potential hazard to the cell. Such lysosomes are therefore engulfed by autophagic membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin-3. Here, we show that, under various conditions that cause injury to the lysosome membrane, components of the endosomal sorting complex required for transport (ESCRT)-I, ESCRT-II, and ESCRT-III are recruited. This recruitment occurs before that of Galectin-3 and the lysophagy machinery. Subunits of ...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Radulovic, M., Schink, K. O., Wenzel, E. M., Nähse, V., Bongiovanni, A., Lafont, F., Stenmark, H. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Mrc1 and Rad9 cooperate to regulate initiation and elongation of DNA replication in response to DNA damage
The S-phase checkpoint maintains the integrity of the genome in response to DNA replication stress. In budding yeast, this pathway is initiated by Mec1 and is amplified through the activation of Rad53 by two checkpoint mediators: Mrc1 promotes Rad53 activation at stalled forks, and Rad9 is a general mediator of the DNA damage response. Here, we have investigated the interplay between Mrc1 and Rad9 in response to DNA damage and found that they control DNA replication through two distinct but complementary mechanisms. Mrc1 rapidly activates Rad53 at stalled forks and represses late-firing origins but is unable to maintain th...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Bacal, J., Moriel-Carretero, M., Pardo, B., Barthe, A., Sharma, S., Chabes, A., Lengronne, A., Pasero, P. Tags: DNA Replication, Repair & Recombination Articles Source Type: research
Nonsense-mediated mRNA decay involves two distinct Upf1-bound complexes
Nonsense-mediated mRNA decay (NMD) is a translation-dependent RNA degradation pathway involved in many cellular pathways and crucial for telomere maintenance and embryo development. Core NMD factors Upf1, Upf2 and Upf3 are conserved from yeast to mammals, but a universal NMD model is lacking. We used affinity purification coupled with mass spectrometry and an improved data analysis protocol to characterize the composition and dynamics of yeast NMD complexes in yeast (112 experiments). Unexpectedly, we identified two distinct complexes associated with Upf1: Upf1-23 (Upf1, Upf2, Upf3) and Upf1-decapping. Upf1-decapping conta...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Dehecq, M., Decourty, L., Namane, A., Proux, C., Kanaan, J., Le Hir, H., Jacquier, A., Saveanu, C. Tags: Protein Biosynthesis & Quality Control, RNA Biology Articles Source Type: research
Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy
PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dyna...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Sugo, M., Kimura, H., Arasaki, K., Amemiya, T., Hirota, N., Dohmae, N., Imai, Y., Inoshita, T., Shiba-Fukushima, K., Hattori, N., Cheng, J., Fujimoto, T., Wakana, Y., Inoue, H., Tagaya, M. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research
Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma
The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a. TSC1 knockdown results in e...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Hartleben, G., Müller, C., Krämer, A., Schimmel, H., Zidek, L. M., Dornblut, C., Winkler, R., Eichwald, S., Kortman, G., Kosan, C., Kluiver, J., Petersen, I., van den Berg, A., Wang, Z.-Q., Calkhoven, C. F. Tags: Cancer, Signal Transduction Articles Source Type: research
Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
Self-renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Es...
Source: EMBO Journal - November 2, 2018 Category: Molecular Biology Authors: Festuccia, N., Halbritter, F., Corsinotti, A., Gagliardi, A., Colby, D., Tomlinson, S. R., Chambers, I. Tags: Development & Differentiation, Stem Cells, Transcription Articles Source Type: research
ATF4-amino acid circuits: a recipe for resistance in melanoma
Lactate dehydrogenase A (LDHA) has appropriately received attention as a therapeutic target for the treatment of a broad spectrum of tumor types, yet little is known regarding intrinsic resistance to LDHA inhibitors. Pathria et al (2018) now establish that ATF4-dependent control of enzymes that direct amino acid metabolism confers resistance to LDHA inhibitors in melanoma and identify chokepoints that can be exploited to overcome metabolic compensation, setting the stage for trials with such combinations. (Source: EMBO Journal)
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Fernandez, M. R., Cleveland, J. L. Tags: Cancer, Metabolism News [amp ] Views Source Type: research
Epigenetically jump starting de novo shoot regeneration
The ability to regenerate lost organs or tissues is a central requirement for animals and plants in order to cope with injury. Regeneration of a whole body is rare in animals but is more commonly found in plants where in vitro regeneration has become a widely used tool in plant research. In a new study, Kim et al find that epigenetic changes via the histone acetyltransferase HAG1 establish the competency for shoot regeneration from callus by promoting the expression of root stem cell factors. (Source: EMBO Journal)
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Zhang, N., Laux, T. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Plant Biology News [amp ] Views Source Type: research
Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by {beta}2 adrenergic receptor/PKA and Ca2+/CaMKII signaling
The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD-95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how β2 adrenergic receptor (β2 AR) signaling via adenylyl cyclase and the cAMP-dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of β2 AR, adenylyl cyclase, a...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Patriarchi, T., Buonarati, O. R., Hell, J. W. Tags: Neuroscience, Signal Transduction Review Source Type: research
Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival
Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular s...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Pathria, G., Scott, D. A., Feng, Y., Sang Lee, J., Fujita, Y., Zhang, G., Sahu, A. D., Ruppin, E., Herlyn, M., Osterman, A. L., Ronai, Z. A. Tags: Cancer, Metabolism, Transcription Articles Source Type: research
Pool size estimations for dense-core vesicles in mammalian CNS neurons
Neuropeptides are essential signaling molecules transported and secreted by dense-core vesicles (DCVs), but the number of DCVs available for secretion, their subcellular distribution, and release probability are unknown. Here, we quantified DCV pool sizes in three types of mammalian CNS neurons in vitro and in vivo. Super-resolution and electron microscopy reveal a total pool of 1,400–18,000 DCVs, correlating with neurite length. Excitatory hippocampal and inhibitory striatal neurons in vitro have a similar DCV density, and thalamo-cortical axons in vivo have a slightly higher density. Synapses co...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Persoon, C. M., Moro, A., Nassal, J. P., Farina, M., Broeke, J. H., Arora, S., Dominguez, N., van Weering, J. R., Toonen, R. F., Verhage, M. Tags: Neuroscience Articles Source Type: research
