A magic bullet for targeting cancers with supernumerary centrosomes
This study demonstrates the potential of developing tumor-specific treatment by specifically targeting centrosome amplification. (Source: EMBO Journal)
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Liu, Y., Pelletier, L. Tags: Cancer, Cell Adhesion, Polarity & Cytoskeleton, Cell Cycle News [amp ] Views Source Type: research
Rethinking research reproducibility
"To boldly go where no man has gone before"! Exploring and innovating—isn't this why we are in science after all? But as exciting this may be, others must be able to confirm our results through competent replication. As Karl Popper famously put it: "Single occurrences that cannot be reproduced are of no significance to science" (Popper, 1935). However, despite its status as a founding principle of modern science, replication is often viewed as pedestrian and unoriginal. Academia rewards the explorer, not the replicator. Not surprisingly, the current biomedical literature is dominated by exploration, but results are r...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Dirnagl, U. Tags: Methods & Resources Commentary Source Type: research
A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease
Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance. However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8-restricted TH1 immune and antibody response leading to celiac disease. Prior epithelial stress and innate immune activation are essential for breaking oral tolerance to the gluten component gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Here, we show that the α-gliadin-derived LGQQQPFPPQQPY peptide (P31–43) inhibits the function of cystic&nbs...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Villella, V. R., Venerando, A., Cozza, G., Esposito, S., Ferrari, E., Monzani, R., Spinella, M. C., Oikonomou, V., Renga, G., Tosco, A., Rossin, F., Guido, S., Silano, M., Garaci, E., Chao, Y.-K., Grimm, C., Luciani, A., Romani, L., Piacentini, M., Raia, Tags: Immunology, Membrane & Intracellular Transport, Molecular Biology of Disease Articles Source Type: research
Precocious expression of Blimp1 in B cells causes autoimmune disease with increased self-reactive plasma cells
The transcription factor Blimp1 is not only an essential regulator of plasma cells, but also a risk factor for the development of autoimmune disease in humans. Here, we demonstrate in the mouse that the Prdm1 (Blimp1) gene was partially activated at the chromatin and transcription level in early B cell development, although mature Prdm1 mRNA did not accumulate due to posttranscriptional regulation. By analyzing a mouse model that facilitated ectopic Blimp1 protein expression throughout B lymphopoiesis, we could demonstrate that Blimp1 impaired B cell development by interfering with the B cell gene expression program, while...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Bönelt, P., Wöhner, M., Minnich, M., Tagoh, H., Fischer, M., Jaritz, M., Kavirayani, A., Garimella, M., Karlsson, M. C., Busslinger, M. Tags: Immunology Articles Source Type: research
Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
We report that following mitochondrial damage-induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3-only proteins and its homo-dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX-mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK-dependent mitochondrial outer membrane permeabilisation during apoptosis promotes...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Bernardini, J. P., Brouwer, J. M., Tan, I. K., Sandow, J. J., Huang, S., Stafford, C. A., Bankovacki, A., Riffkin, C. D., Wardak, A. Z., Czabotar, P. E., Lazarou, M., Dewson, G. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
An inter-dimer allosteric switch controls NMDA receptor activity
NMDA receptors (NMDARs) are glutamate-gated ion channels that are key mediators of excitatory neurotransmission and synaptic plasticity throughout the central nervous system. They form massive heterotetrameric complexes endowed with unique allosteric capacity provided by eight extracellular clamshell-like domains arranged as two superimposed layers. Despite an increasing number of full-length NMDAR structures, how these domains cooperate in an intact receptor to control its activity remains poorly understood. Here, combining single-molecule and macroscopic electrophysiological recordings, cysteine biochemistry, and in sili...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Esmenjaud, J.-B., Stroebel, D., Chan, K., Grand, T., David, M., Wollmuth, L. P., Taly, A., Paoletti, P. Tags: Neuroscience, Structural Biology Articles Source Type: research
Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells
Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP–tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of C...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Mariappan, A., Soni, K., Schorpp, K., Zhao, F., Minakar, A., Zheng, X., Mandad, S., Macheleidt, I., Ramani, A., Kubelka, T., Dawidowski, M., Golfmann, K., Wason, A., Yang, C., Simons, J., Schmalz, H.-G., Hyman, A. A., Aneja, R., Ullrich, R., Urlaub, H., O Tags: Cancer, Cell Adhesion, Polarity & Cytoskeleton, Cell Cycle Articles Source Type: research
A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex
Autophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR-Cas9 or knockout-mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone Calnexin (CANX) and the ER-...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Forrester, A., De Leonibus, C., Grumati, P., Fasana, E., Piemontese, M., Staiano, L., Fregno, I., Raimondi, A., Marazza, A., Bruno, G., Iavazzo, M., Intartaglia, D., Seczynska, M., van Anken, E., Conte, I., De Matteis, M. A., Dikic, I., Molinari, M., Sett Tags: Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research
Prominin-1 controls stem cell activation by orchestrating ciliary dynamics
Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly–disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and trans...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Singer, D., Thamm, K., Zhuang, H., Karbanova, J., Gao, Y., Walker, J. V., Jin, H., Wu, X., Coveney, C. R., Marangoni, P., Lu, D., Grayson, P. R. C., Gulsen, T., Liu, K. J., Ardu, S., Wann, A. K., Luo, S., Zambon, A. C., Jetten, A. M., Tredwin, C., Klein, Tags: Cell Adhesion, Polarity & Cytoskeleton, Development & Differentiation, Stem Cells Articles Source Type: research
Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders
Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann–Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal deat...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Gabande-Rodriguez, E., Perez-Canamas, A., Soto-Huelin, B., Mitroi, D. N., Sanchez-Redondo, S., Martinez-Saez, E., Venero, C., Peinado, H., Ledesma, M. D. Tags: Membrane & Intracellular Transport, Neuroscience Articles Source Type: research
Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca2+ levels and tumor growth
Although mitochondria play a multifunctional role in cancer progression and Ca2+ signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca2+ homeostasis with malignant tumor formation and growth remain elusive. Here, we show that phosphorylation at the N-terminal region of the mitochondrial calcium uniporter (MCU) regulatory subunit MICU1 leads to a notable increase in the basal mitochondrial Ca2+ levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion-targeted Akt strongly regulates the mitochondrial Ca2+ content. The Akt-m...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Marchi, S., Corricelli, M., Branchini, A., Vitto, V. A. M., Missiroli, S., Morciano, G., Perrone, M., Ferrarese, M., Giorgi, C., Pinotti, M., Galluzzi, L., Kroemer, G., Pinton, P. Tags: Cancer, Membrane & Intracellular Transport Articles Source Type: research
Miro proteins prime mitochondria for Parkin translocation and mitophagy
The Parkinson's disease-associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool ...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Safiulina, D., Kuum, M., Choubey, V., Gogichaishvili, N., Liiv, J., Hickey, M. A., Cagalinec, M., Mandel, M., Zeb, A., Liiv, M., Kaasik, A. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research
Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth
Vascular endothelial growth factor receptor-3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell-specific depletion of integrin-linked kinase (ILK) in mouse embryos hyper-activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)-specific deletion of Ilk in adult mice ...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Urner, S., Planas-Paz, L., Hilger, L. S., Henning, C., Branopolski, A., Kelly-Goss, M., Stanczuk, L., Pitter, B., Montanez, E., Peirce, S. M., Mäkinen, T., Lammert, E. Tags: Development & Differentiation, Signal Transduction, Vascular Biology & Angiogenesis Articles Source Type: research
TCF/LEF dependent and independent transcriptional regulation of Wnt/{beta}-catenin target genes
During canonical Wnt signalling, the activity of nuclear β-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of β-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that β-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed ...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Doumpas, N., Lampart, F., Robinson, M. D., Lentini, A., Nestor, C. E., Cantu, C., Basler, K. Tags: Signal Transduction, Transcription Articles Source Type: research
SUMOning the base excision repair machinery for differentiation
Besides critical and well-studied roles in maintaining genome stability, DNA repair pathways including base excision repair (BER) are also employed by mammalian cells for targeted events such as the generation of diverse antibody repertoires and the differentiation of pluripotent cells. In this issue of The EMBO Journal, Steinacher et al (2019) provide novel mechanistic insights into the complex role of SUMOylation of key BER proteins during active DNA demethylation—a role they demonstrate to be important for cellular differentiation and that has broader implications for BER as a whole. (Source: EMBO Journal)
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Wiest, N. E., Tomkinson, A. E. Tags: Development & Differentiation, DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research
