Programmed mitophagy is essential for the glycolytic switch during cell differentiation
Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator B...
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Esteban-Martinez, L., Sierra-Filardi, E., McGreal, R. S., Salazar-Roa, M., Marino, G., Seco, E., Durand, S., Enot, D., Grana, O., Malumbres, M., Cvekl, A., Cuervo, A. M., Kroemer, G., Boya, P. Tags: Autophagy & Cell Death, Metabolism, Neuroscience Articles Source Type: research

An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function
Stress granules (SG) are membrane-less compartments involved in regulating mRNAs during stress. Aberrant forms of SGs have been implicated in age-related diseases, such as amyotrophic lateral sclerosis (ALS), but the molecular events triggering their formation are still unknown. Here, we find that misfolded proteins, such as ALS-linked variants of SOD1, specifically accumulate and aggregate within SGs in human cells. This decreases the dynamics of SGs, changes SG composition, and triggers an aberrant liquid-to-solid transition of in vitro reconstituted compartments. We show that chaperone recruitment prevents the form...
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Mateju, D., Franzmann, T. M., Patel, A., Kopach, A., Boczek, E. E., Maharana, S., Lee, H. O., Carra, S., Hyman, A. A., Alberti, S. Tags: Membrane & Intracellular Transport, Protein Biosynthesis & Quality Control, RNA Biology Articles Source Type: research

Zika virus induces massive cytoplasmic vacuolization and paraptosis-like death in infected cells
We report that ZIKV induces massive vacuolization followed by "implosive" cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low. It is reminiscent of paraptosis, a caspase-independent, non-apoptotic form of cell death associated with the formation of large cytoplasmic vacuoles. We further show that ZIKV-induced vacuoles are derived from the endoplasmic reticulum (ER) and dependent on the PI3K/Akt signaling axis. Inhibiting the Sec61 ER translocon in ZIKV-infected cells blocked vacuole formation and viral production. Our results ...
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Monel, B., Compton, A. A., Bruel, T., Amraoui, S., Burlaud-Gaillard, J., Roy, N., Guivel-Benhassine, F., Porrot, F., Genin, P., Meertens, L., Sinigaglia, L., Jouvenet, N., Weil, R., Casartelli, N., Demangel, C., Simon-Loriere, E., Moris, A., Roingeard, P. Tags: Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research

NIX-ing mitochondria: from development to pathology
Hypoxia occurs physiologically in the developing body, and changing oxygen tensions are known to direct tissue differentiation; however, in the context of pathology, the same hypoxia-activated mechanisms may negatively affect tissue function. In this issue of The EMBO Journal, Esteban-Martínez et al (2017) report that programmed mitophagy, dependent on hypoxia-induced NIP-3-like protein X (BNIP3L, best known as NIX), is an essential step in differentiation of both retinal neurons and inflammatory macrophages. (Source: EMBO Journal)
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Deczkowska, A., Schwartz, M. Tags: Autophagy & Cell Death, Development & Differentiation, Metabolism News [amp ] Views Source Type: research

Getting stress out of stressed-out stress granules
Amyotrophic lateral sclerosis (ALS) pathology is linked to the aberrant aggregation of specific proteins, including TDP-43, FUS, and SOD1, but it is not clear why these aggregation events cause ALS. In this issue of The EMBO Journal, Mateju et al (2017) report a direct link between misfolded proteins accumulating in stress granules and the phase transition of these stress granules from liquid to solid. This discovery provides a model connecting protein aggregation to stress granule dysfunction. (Source: EMBO Journal)
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Siwach, P., Kaganovich, D. Tags: Membrane & Intracellular Transport, Protein Biosynthesis & Quality Control, RNA Biology News [amp ] Views Source Type: research

Is magnetogenetics the new optogenetics?
Optogenetics has revolutionised neuroscience as it enables investigators to establish causal relationships between neuronal activity and a behavioural outcome in a temporally precise manner. It is a powerful technology, but limited by the necessity to deliver light to the cells of interest, which often requires invasive surgery and a tethered light source. Magnetogenetics aims to overcome these issues by manipulating neurons with magnetic stimuli. As magnetic fields can pass freely through organic tissue, it requires no surgery or tethering the animals to an energy source. In this commentary, we assess the utility of ...
Source: EMBO Journal - June 14, 2017 Category: Molecular Biology Authors: Nimpf, S., Keays, D. A. Tags: Neuroscience Commentary Source Type: research

Plant virus-mediated induction of miR168 is associated with repression of ARGONAUTE1 accumulation
(Source: EMBO Journal)
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Varallyay, E., Valoczi, A., Agyi, A., Burgyan, J., Havelda, Z. Tags: RNA Biology Corrigenda Source Type: research

BAX inhibitor-1 regulates autophagy by controlling the IRE1{alpha} branch of the unfolded protein response
(Source: EMBO Journal)
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Castillo, K., Rojas-Rivera, D., Lisbona, F., Caballero, B., Nassif, M., Court, F. A., Schuck, S., Ibar, C., Walter, P., Sierralta, J., Glavic, A., Hetz, C. Tags: Corrigenda Source Type: research

USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling
SMAD4 is a common intracellular effector for TGF-β family cytokines, but the mechanism by which its activity is dynamically regulated is unclear. We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4. This modification was triggered by the recruitment of the E3 ligase, SMURF2, to SMAD4 following ligand-induced regulatory (R)-SMAD–SMAD4 complex formation. Whereas the interaction of the negative regulator c-SKI inhibits SMAD4 monoubiquitination, the ligand stimulates the recruitment of SMURF2 to the c-SKI-SMAD2 compl...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Zhou, F., Xie, F., Jin, K., Zhang, Z., Clerici, M., Gao, R., van Dinther, M., Sixma, T. K., Huang, H., Zhang, L., ten Dijke, P. Tags: Development & Differentiation, Signal Transduction Articles Source Type: research

A new sub-pathway of long-patch base excision repair involving 5' gap formation
Base excision repair (BER) is one of the most frequently used cellular DNA repair mechanisms and modulates many human pathophysiological conditions related to DNA damage. Through live cell and in vitro reconstitution experiments, we have discovered a major sub-pathway of conventional long-patch BER that involves formation of a 9-nucleotide gap 5' to the lesion. This new sub-pathway is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 poly(ADP-ribose) polymerase and RPA. The novel gap formation step is employed during repair of a variety of DNA lesions, including oxidative and alkylati...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Woodrick, J., Gupta, S., Camacho, S., Parvathaneni, S., Choudhury, S., Cheema, A., Bai, Y., Khatkar, P., Erkizan, H. V., Sami, F., Su, Y., Schärer, O. D., Sharma, S., Roy, R. Tags: DNA Replication, Repair & Recombination Articles Source Type: research

Sen1 has unique structural features grafted on the architecture of the Upf1-like helicase family
The superfamily 1B (SF1B) helicase Sen1 is an essential protein that plays a key role in the termination of non-coding transcription in yeast. Here, we identified the ~90 kDa helicase core of Saccharomyces cerevisiae Sen1 as sufficient for transcription termination in vitro and determined the corresponding structure at 1.8 Å resolution. In addition to the catalytic and auxiliary subdomains characteristic of the SF1B family, Sen1 has a distinct and evolutionarily conserved structural feature that "braces" the helicase core. Comparative structural analyses indicate that the "brace" is...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Leonaite, B., Han, Z., Basquin, J., Bonneau, F., Libri, D., Porrua, O., Conti, E. Tags: RNA Biology, Structural Biology Articles Source Type: research

Short FtsZ filaments can drive asymmetric cell envelope constriction at the onset of bacterial cytokinesis
FtsZ, the bacterial homologue of eukaryotic tubulin, plays a central role in cell division in nearly all bacteria and many archaea. It forms filaments under the cytoplasmic membrane at the division site where, together with other proteins it recruits, it drives peptidoglycan synthesis and constricts the cell. Despite extensive study, the arrangement of FtsZ filaments and their role in division continue to be debated. Here, we apply electron cryotomography to image the native structure of intact dividing cells and show that constriction in a variety of Gram-negative bacterial cells, including Proteus mirabilis and Caulobact...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Yao, Q., Jewett, A. I., Chang, Y.-W., Oikonomou, C. M., Beeby, M., Iancu, C. V., Briegel, A., Ghosal, D., Jensen, G. J. Tags: Cell Adhesion, Polarity & Cytoskeleton, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research

The transcription factor bZIP14 regulates the TCA cycle in the diatom Phaeodactylum tricornutum
Diatoms are amongst the most important marine microalgae in terms of biomass, but little is known concerning the molecular mechanisms that regulate their versatile metabolism. Here, the pennate diatom Phaeodactylum tricornutum was studied at the metabolite and transcriptome level during nitrogen starvation and following imposition of three other stresses that impede growth. The coordinated upregulation of the tricarboxylic acid (TCA) cycle during the nitrogen stress response was the most striking observation. Through co-expression analysis and DNA binding assays, the transcription factor bZIP14 was identified as a regulato...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Matthijs, M., Fabris, M., Obata, T., Foubert, I., Franco-Zorrilla, J. M., Solano, R., Fernie, A. R., Vyverman, W., Goossens, A. Tags: Plant Biology Articles Source Type: research

Mfn2 is critical for brown adipose tissue thermogenic function
Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin-resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific Mfn2 knockout (Mfn2-adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity a...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Boutant, M., Kulkarni, S. S., Joffraud, M., Ratajczak, J., Valera-Alberni, M., Combe, R., Zorzano, A., Canto, C. Tags: Membrane & Intracellular Transport, Metabolism Articles Source Type: research

PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing
Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat-specific genes while repressing white fat and muscle-specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)-stimulated genes (ISGs), including Stat1, in adipocytes in vitro and in vivo. Ectopic activation of type I IFN signaling in brown adipoc...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Kissig, M., Ishibashi, J., Harms, M. J., Lim, H.-W., Stine, R. R., Won, K.-J., Seale, P. Tags: Immunology, Metabolism Articles Source Type: research

Drosophila Dalmatian combines sororin and shugoshin roles in establishment and protection of cohesion
Sister chromatid cohesion is crucial to ensure chromosome bi-orientation and equal chromosome segregation. Cohesin removal via mitotic kinases and Wapl has to be prevented in pericentromeric regions in order to protect cohesion until metaphase, but the mechanisms of mitotic cohesion protection remain elusive in Drosophila. Here, we show that dalmatian (Dmt), an ortholog of the vertebrate cohesin-associated protein sororin, is required for protection of mitotic cohesion in flies. Dmt is essential for cohesion establishment during interphase and is enriched on pericentromeric heterochromatin. Dmt is recruited through direct ...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Yamada, T., Tahara, E., Kanke, M., Kuwata, K., Nishiyama, T. Tags: Cell Cycle Articles Source Type: research

ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells
Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER–mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER–mitochondria contacts compared to GDCs. Forced ER–mitochondria contacts in G...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Bassoy, E. Y., Kasahara, A., Chiusolo, V., Jacquemin, G., Boydell, E., Zamorano, S., Riccadonna, C., Pellegatta, S., Hulo, N., Dutoit, V., Derouazi, M., Dietrich, P. Y., Walker, P. R., Martinvalet, D. Tags: Cancer, Immunology, Metabolism Articles Source Type: research

Brain metabolism in health, aging, and neurodegeneration
Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, an...
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Camandola, S., Mattson, M. P. Tags: Metabolism, Neuroscience Review Source Type: research

Gene body DNA methylation conspires with H3K36me3 to preclude aberrant transcription
DNA methylation of promoters is well known for its repressive effect on transcription initiation of protein-coding genes, non-coding RNAs, or transposon repeats. However, gene bodies represent the most conserved targets of DNA methylation among eukaryotes, and yet the function of intragenic methylation remains unclear. Recent research (Neri et al, 2017) suggests that intragenic methylation may serve to confine transcription initiation to canonical promoters in embryonic stem cells, thus preventing the production of aberrant transcripts. (Source: EMBO Journal)
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Teissandier, A., Bourc'his, D. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Stem Cells, Transcription News [amp ] Views Source Type: research

Dalmatian: spotting the difference in cohesin protectors
The cohesin complex prevents separation of chromosomes following their duplication until the appropriate time during cell division. In vertebrates, establishment and maintenance of cohesin-dependent linkages depend on two distinct proteins, sororin and shugoshin. New findings published in The EMBO Journal show that in Drosophila, the function of both of these cohesin regulators is carried out by a single hybrid protein, Dalmatian. (Source: EMBO Journal)
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Marston, A. L. Tags: Cell Cycle News [amp ] Views Source Type: research

Judging a tumor cell by its cover: a matter of mitochondrial contact sites
Glioblastoma is a highly aggressive brain tumor constituted by glioma stem cell and differentiated cell populations with distinct susceptibility to cytotoxic T lymphocytes crucial for tumor immune surveillance. In this issue of The EMBO Journal, Bassoy et al (2017) show that the surface expression of certain glycans that favor recognition and killing by T cells depends on mitochondrial contacts with the endoplasmic reticulum, extending the function of this interface even to immune recognition. (Source: EMBO Journal)
Source: EMBO Journal - June 1, 2017 Category: Molecular Biology Authors: Lakshminarayanan, S., Scorrano, L. Tags: Cancer, Immunology, Metabolism News [amp ] Views Source Type: research

Endothelial basement membrane laminin 511 is essential for shear stress response
(Source: EMBO Journal)
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Di Russo, J., Luik, A.-L., Yousif, L., Budny, S., Oberleithner, H., Hofschröer, V., Klingauf, J., van Bavel, E., Bakker, E. N., Hellstrand, P., Bhattachariya, A., Albinsson, S., Pincet, F., Hallmann, R., Sorokin, L. M. Tags: Cell Adhesion, Polarity & Cytoskeleton, Vascular Biology & Angiogenesis Corrigenda Source Type: research

Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells
(Source: EMBO Journal)
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Guidi, N., Sacma, M., Ständker, L., Soller, K., Marka, G., Eiwen, K., Weiss, J. M., Kirchhoff, F., Weil, T., Cancelas, J. A., Florian, M. C., Geiger, H. Tags: Ageing, Cell Adhesion, Polarity & Cytoskeleton, Stem Cells Corrigenda Source Type: research

Unusual semi-extractability as a hallmark of nuclear body-associated architectural noncoding RNAs
NEAT1_2 long noncoding RNA (lncRNA) is the molecular scaffold of paraspeckle nuclear bodies. Here, we report an improved RNA extraction method: extensive needle shearing or heating of cell lysate in RNA extraction reagent improved NEAT1_2 extraction by 20-fold (a property we term "semi-extractability"), whereas using a conventional method NEAT1_2 was trapped in the protein phase. The improved extraction method enabled us to estimate that approximately 50 NEAT1_2 molecules are present in a single paraspeckle. Another architectural lncRNA, IGS16, also exhibited similar semi-extractability. A comparison of RNA-seq d...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Chujo, T., Yamazaki, T., Kawaguchi, T., Kurosaka, S., Takumi, T., Nakagawa, S., Hirose, T. Tags: Methods & Resources, Protein Biosynthesis & Quality Control, RNA Biology Source Type: research

USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling
The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway. Mechanistically, USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances P...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Luo, K., Li, Y., Yin, Y., Li, L., Wu, C., Chen, Y., Nowsheen, S., Hu, Q., Zhang, L., Lou, Z., Yuan, J. Tags: Cancer, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research

STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites
StAR-related lipid transfer domain-3 (STARD3) is a sterol-binding protein that creates endoplasmic reticulum (ER)–endosome contact sites. How this protein, at the crossroad between sterol uptake and synthesis pathways, impacts the intracellular distribution of this lipid was ill-defined. Here, by using in situ cholesterol labeling and quantification, we demonstrated that STARD3 induces cholesterol accumulation in endosomes at the expense of the plasma membrane. STARD3-mediated cholesterol routing depends both on its lipid transfer activity and its ability to create ER–endosome contacts. Corroborating this,...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Wilhelm, L. P., Wendling, C., Vedie, B., Kobayashi, T., Chenard, M.-P., Tomasetto, C., Drin, G., Alpy, F. Tags: Membrane & Intracellular Transport Articles Source Type: research

The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals
Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advance...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Vanhauwaert, R., Kuenen, S., Masius, R., Bademosi, A., Manetsberger, J., Schoovaerts, N., Bounti, L., Gontcharenko, S., Swerts, J., Vilain, S., Picillo, M., Barone, P., Munshi, S. T., de Vrij, F. M., Kushner, S. A., Gounko, N. V., Mandemakers, W., Bonifat Tags: Autophagy & Cell Death, Neuroscience Articles Source Type: research

let-7 regulates radial migration of new-born neurons through positive regulation of autophagy
During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB. Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2 immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family. Knockdown of let-7 in migrating neuroblasts prevented radial migration and led to an immature mo...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Petri, R., Pircs, K., Jönsson, M. E., Akerblom, M., Brattas, P. L., Klussendorf, T., Jakobsson, J. Tags: Development & Differentiation, Neuroscience Articles Source Type: research

A second Wpl1 anti-cohesion pathway requires dephosphorylation of fission yeast kleisin Rad21 by PP4
We report here that Wpl1 anti-cohesion function includes an additional mechanism. A genetic screen uncovered that Protein Phosphatase 4 (PP4) mutants allowed cell survival in the complete absence of Eso1. PP4 co-immunoprecipitated Wpl1 and cohesin and Wpl1 triggered Rad21 de-phosphorylation in a PP4-dependent manner. Relevant residues were identified and mapped within the central domain of Rad21. Phospho-mimicking alleles dampened Wpl1 anti-cohesion activity, while alanine mutants were neutral indicating that Rad21 phosphorylation would shelter cohesin from Wpl1 unless erased by PP4. Experiments in post-replicative cells l...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Birot, A., Eguienta, K., Vazquez, S., Claverol, S., Bonneu, M., Ekwall, K., Javerzat, J.-P., Vaur, S. Tags: Cell Cycle, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

Hypoxia enhances antibody-dependent dengue virus infection
Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post-mortem analysis. These organs are known to have low oxygen levels (~0.5–4.5% O2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia-induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2 show greater susceptibility to antibody-dependent enhancement of DENV infection. Low oxygen level induces HIF1α-dependent upregulation of fragment crystallizable gamma receptor IIA (FcRIIA) as well as HIF...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Gan, E. S., Cheong, W. F., Chan, K. R., Ong, E. Z., Chai, X., Tan, H. C., Ghosh, S., Wenk, M. R., Ooi, E. E. Tags: Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research

Fatty acid synthesis is critical for stem cell pluripotency via promoting mitochondrial fission
Pluripotent stem cells are known to display distinct metabolic phenotypes than their somatic counterparts. While accumulating studies are focused on the roles of glucose and amino acid metabolism in facilitating pluripotency, little is known regarding the role of lipid metabolism in regulation of stem cell activities. Here, we show that fatty acid (FA) synthesis activation is critical for stem cell pluripotency. Our initial observations demonstrated enhanced lipogenesis in pluripotent cells and during cellular reprogramming. Further analysis indicated that de novo FA synthesis controls cellular reprogramming and embryonic ...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Wang, L., Zhang, T., Wang, L., Cai, Y., Zhong, X., He, X., Hu, L., Tian, S., Wu, M., Hui, L., Zhang, H., Gao, P. Tags: Metabolism, Stem Cells Articles Source Type: research

Self-organized developmental patterning and differentiation in cerebral organoids
Cerebral organoids recapitulate human brain development at a considerable level of detail, even in the absence of externally added signaling factors. The patterning events driving this self-organization are currently unknown. Here, we examine the developmental and differentiative capacity of cerebral organoids. Focusing on forebrain regions, we demonstrate the presence of a variety of discrete ventral and dorsal regions. Clearing and subsequent 3D reconstruction of entire organoids reveal that many of these regions are interconnected, suggesting that the entire range of dorso-ventral identities can be generated within cont...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Renner, M., Lancaster, M. A., Bian, S., Choi, H., Ku, T., Peer, A., Chung, K., Knoblich, J. A. Tags: Development & Differentiation Articles Source Type: research

Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine
Biochemistry textbooks and cell culture experiments seem to be telling us two different things about the significance of external glutamine supply for mammalian cell growth and proliferation. Despite the fact that glutamine is a nonessential amino acid that can be synthesized by cells from glucose-derived carbons and amino acid-derived ammonia, most mammalian cells in tissue culture cannot proliferate or even survive in an environment that does not contain millimolar levels of glutamine. Not only are the levels of glutamine in standard tissue culture media at least ten-fold higher than other amino acids, but glutamine is a...
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Zhang, J., Pavlova, N. N., Thompson, C. B. Tags: Cancer, Metabolism Review Source Type: research

Revealing the inner workings of organoids
The mechanisms by which human stem cells self-organise into brain-like tissues in 3D organoid culture are poorly understood. In this issue of The EMBO Journal, Renner and Lancaster et al demonstrate that in the absence of external stimuli, human cerebral organoids develop large forebrain structures that display specific landmarks of spatial and temporal patterning, including signalling centres producing known morphogens. The generation of cerebral organoids is therefore likely to reflect normal brain development. (Source: EMBO Journal)
Source: EMBO Journal - May 15, 2017 Category: Molecular Biology Authors: Dias, C., Guillemot, F. Tags: Development & Differentiation News [amp ] Views Source Type: research

The retinoblastoma homolog RBR1 mediates localization of the repair protein RAD51 to DNA lesions in Arabidopsis
The retinoblastoma protein (Rb), which typically functions as a transcriptional repressor of E2F-regulated genes, represents a major control hub of the cell cycle. Here, we show that loss of the Arabidopsis Rb homolog RETINOBLASTOMA-RELATED 1 (RBR1) leads to cell death, especially upon exposure to genotoxic drugs such as the environmental toxin aluminum. While cell death can be suppressed by reduced cell-proliferation rates, rbr1 mutant cells exhibit elevated levels of DNA lesions, indicating a direct role of RBR1 in the DNA-damage response (DDR). Consistent with its role as a transcriptional repressor, we find that RBR1 d...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Biedermann, S., Harashima, H., Chen, P., Heese, M., Bouyer, D., Sofroni, K., Schnittger, A. Tags: Cell Cycle, DNA Replication, Repair & Recombination, Plant Biology Articles Source Type: research

Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control
The rapidly proliferating cells in plant meristems must be protected from genome damage. Here, we show that the regulatory role of the Arabidopsis RETINOBLASTOMA RELATED (RBR) in cell proliferation can be separated from a novel function in safeguarding genome integrity. Upon DNA damage, RBR and its binding partner E2FA are recruited to heterochromatic H2AX-labelled DNA damage foci in an ATM- and ATR-dependent manner. These H2AX-labelled DNA lesions are more dispersedly occupied by the conserved repair protein, AtBRCA1, which can also co-localise with RBR foci. RBR and AtBRCA1 physically interact in vitro and in planta...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Horvath, B. M., Kourova, H., Nagy, S., Nemeth, E., Magyar, Z., Papdi, C., Ahmad, Z., Sanchez-Perez, G. F., Perilli, S., Blilou, I., Pettko-Szandtner, A., Darula, Z., Meszaros, T., Binarova, P., Bogre, L., Scheres, B. Tags: Cell Cycle, DNA Replication, Repair & Recombination, Plant Biology Articles Source Type: research

A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination
Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2- and methyltransferase-independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2-targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2-SET domain, triggering E...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Wang, X., Cao, W., Zhang, J., Yan, M., Xu, Q., Wu, X., Wan, L., Zhang, Z., Zhang, C., Qin, X., Xiao, M., Ye, D., Liu, Y., Han, Z., Wang, S., Mao, L., Wei, W., Chen, W. Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment
In this study, we demonstrate that in vivo knockdown of microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of AnkG locali...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Satake, T., Yamashita, K., Hayashi, K., Miyatake, S., Tamura-Nakano, M., Doi, H., Furuta, Y., Shioi, G., Miura, E., Takeo, Y. H., Yoshida, K., Yahikozawa, H., Matsumoto, N., Yuzaki, M., Suzuki, A. Tags: Neuroscience Articles Source Type: research

miR-31 mutants reveal continuous glial homeostasis in the adult Drosophila brain
The study of adult neural cell production has concentrated on neurogenesis. The mechanisms controlling adult gliogenesis are still poorly understood. Here, we provide evidence for a homeostatic process that maintains the population of glial cells in the Drosophila adult brain. Flies lacking microRNA miR-31a start adult life with a normal complement of glia, but transiently lose glia due to apoptosis. miR-31a expression identifies a subset of predominantly gliogenic adult neural progenitor cells. Failure to limit expression of the predicted E3 ubiquitin ligase, Rchy1, in these cells results in glial loss. After an initial d...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Foo, L. C., Song, S., Cohen, S. M. Tags: Development & Differentiation, Neuroscience Articles Source Type: research

Sex-specific, reciprocal regulation of ER{alpha} and miR-22 controls muscle lipid metabolism in male mice
Control of energy homeostasis and metabolism is achieved by integrating numerous pathways, and miRNAs are involved in this process by regulating expression of multiple target genes. However, relatively little is known about the posttranscriptional processing of miRNAs and a potential role for the precursors they derive from. Here, we demonstrate that mature miRNA-22 is more abundant in muscle from male mice relative to females and that this enables sex-specific regulation of muscular lipid metabolism and body weight by repressing estrogen receptor alpha (ERα) expression. We found that the ERα adjusts its own ac...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Schweisgut, J., Schutt, C., Wüst, S., Wietelmann, A., Ghesquiere, B., Carmeliet, P., Dröse, S., Korach, K. S., Braun, T., Boettger, T. Tags: Metabolism, RNA Biology Articles Source Type: research

An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism
Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Hodroj, D., Recolin, B., Serhal, K., Martinez, S., Tsanov, N., Abou Merhi, R., Maiorano, D. Tags: DNA Replication, Repair & Recombination, RNA Biology Articles Source Type: research

Rae1/YacP, a new endoribonuclease involved in ribosome-dependent mRNA decay in Bacillus subtilis
We present a docking model of Rae1 bound to the B. subtilis ribosomal A-site that is consistent with this hypothesis and show that Rae1 cleaves optimally immediately upstream of a lysine codon (AAA or AAG) in vivo. (Source: EMBO Journal)
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Leroy, M., Piton, J., Gilet, L., Pellegrini, O., Proux, C., Coppee, J.-Y., Figaro, S., Condon, C. Tags: Microbiology, Virology & Host Pathogen Interaction, Protein Biosynthesis & Quality Control, RNA Biology Articles Source Type: research

The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo. LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II. In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptos...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Lafont, E., Kantari-Mimoun, C., Draber, P., De Miguel, D., Hartwig, T., Reichert, M., Kupka, S., Shimizu, Y., Taraborrelli, L., Spit, M., Sprick, M. R., Walczak, H. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

Uncoupling of neurogenesis and differentiation during retinal development
Conventionally, neuronal development is regarded to follow a stereotypic sequence of neurogenesis, migration, and differentiation. We demonstrate that this notion is not a general principle of neuronal development by documenting the timing of mitosis in relation to multiple differentiation events for bipolar cells (BCs) in the zebrafish retina using in vivo imaging. We found that BC progenitors undergo terminal neurogenic divisions while in markedly disparate stages of neuronal differentiation. Remarkably, the differentiation state of individual BC progenitors at mitosis is not arbitrary but matches the differentiatio...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Engerer, P., Suzuki, S. C., Yoshimatsu, T., Chapouton, P., Obeng, N., Odermatt, B., Williams, P. R., Misgeld, T., Godinho, L. Tags: Development & Differentiation, Neuroscience Articles Source Type: research

Non-coding RNAs: the dark side of nuclear-mitochondrial communication
Mitochondria are critical hubs for the integration of several key metabolic processes implicated in cell growth and survival. They originated from bacterial ancestors through endosymbiosis, following the transfer of more than 90% of their endosymbiont genome to the host cell nucleus. Over time, a mutually beneficial symbiotic relationship has been established, which relies on continuous and elaborate signaling mechanisms between this life-essential organelle and its host. The ability of mitochondria to signal their functional state and trigger compensatory and adaptive cellular responses has long been recognized, but the u...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Vendramin, R., Marine, J.-C., Leucci, E. Tags: Metabolism, RNA Biology, Signal Transduction Review Source Type: research

Cut in translation: ribosome-dependent mRNA decay
Transcription and translation are two complex mechanisms that are tightly coupled in prokaryotic cells. Even before the completion of transcription, ribosomes attach to the nascent mRNA and initiate protein synthesis. Remarkably, recent publications have indicated an association between translation and decay of certain mRNAs. In this issue of The EMBO Journal, Leroy et al (2017) depicts a fascinating mechanism of mRNA degradation, which involves the ribosome-associated ribonuclease Rae1 in Bacillus subtilis. In a translation-dependent manner, Rae1 binds the ribosomal aminoacylation (A)-site and cleaves between specifi...
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Lalaouna, D., Masse, E. Tags: Microbiology, Virology & Host Pathogen Interaction, Protein Biosynthesis & Quality Control, RNA Biology News [amp ] Views Source Type: research

TRAIL- and TNF-induced signaling complexes--so similar yet so different
TNF receptor-1 (TNFR1) and TRAIL death receptors preferentially induce pro-inflammatory or cytotoxic signaling, respectively, via distinct plasma membrane and cytosolic complexes. New studies identifying the pro-inflammatory factors TRAF2, RIP, and LUBAC in TRAIL death receptor complexes suggest that the latter are more "TNFR1-like" than anticipated and argue for revision of prevailing models of spatio-hierarchical TRAIL-induced signaling complex assembly. (Source: EMBO Journal)
Source: EMBO Journal - May 2, 2017 Category: Molecular Biology Authors: Wajant, H. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research

Development of LC3/GABARAP sensors containing a LIR and a hydrophobic domain to monitor autophagy
Macroautophagy allows for bulk degradation of cytosolic components in lysosomes. Overexpression of GFP/RFP-LC3/GABARAP is commonly used to monitor autophagosomes, a hallmark of autophagy, despite artifacts related to their overexpression. Here, we developed new sensors that detect endogenous LC3/GABARAP proteins at the autophagosome using an LC3-interacting region (LIR) and a short hydrophobic domain (HyD). Among HyD-LIR-GFP sensors harboring LIR motifs of 34 known LC3-binding proteins, HyD-LIR(TP)-GFP using the LIR motif from TP53INP2 allowed detection of all LC3/GABARAPs-positive autophagosomes. However, HyD-LIR(TP)-GFP ...
Source: EMBO Journal - April 13, 2017 Category: Molecular Biology Authors: Lee, Y.-K., Jun, Y.-W., Choi, H.-E., Huh, Y. H., Kaang, B.-K., Jang, D.-J., Lee, J.-A. Tags: Autophagy & Cell Death Resource Source Type: research

Functional and structural insight into properdin control of complement alternative pathway amplification
We describe here a novel FP deficiency (E244K) caused by a single point mutation which results in a very low level of AP activity. Recombinant FP E244K is monomeric, fails to support bacteriolysis, and binds weakly to C3 products. We compare this to a monomeric unit excised from oligomeric FP, which is also dysfunctional in bacteriolysis but binds the AP proconvertase, C3 convertase, C3 products and partially stabilizes the convertase. The crystal structure of such a FP-convertase complex suggests that the major contact between FP and the AP convertase is mediated by a single FP thrombospondin repeat and a small region in ...
Source: EMBO Journal - April 13, 2017 Category: Molecular Biology Authors: Pedersen, D. V., Roumenina, L., Jensen, R. K., Gadeberg, T. A., Marinozzi, C., Picard, C., Rybkine, T., Thiel, S., Sorensen, U. B., Stover, C., Fremeaux-Bacchi, V., Andersen, G. R. Tags: Immunology, Structural Biology Articles Source Type: research

Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4
The SUMO-targeted ubiquitin ligase RNF4 functions at the crossroads of the SUMO and ubiquitin systems. Here, we report that the deubiquitylation enzyme (DUB) ataxin-3 counteracts RNF4 activity during the DNA double-strand break (DSB) response. We find that ataxin-3 negatively regulates ubiquitylation of the checkpoint mediator MDC1, a known RNF4 substrate. Loss of ataxin-3 markedly decreases the chromatin dwell time of MDC1 at DSBs, which can be fully reversed by co-depletion of RNF4. Ataxin-3 is recruited to DSBs in a SUMOylation-dependent fashion, and in vitro it directly interacts with and is stimulated by recombin...
Source: EMBO Journal - April 13, 2017 Category: Molecular Biology Authors: Pfeiffer, A., Luijsterburg, M. S., Acs, K., Wiegant, W. W., Helfricht, A., Herzog, L. K., Minoia, M., Böttcher, C., Salomons, F. A., van Attikum, H., Dantuma, N. P. Tags: DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research