Asymmetric distribution of glucose transporter mRNA provides a growth advantage in yeast
Asymmetric localization of mRNA is important for cell fate decisions in eukaryotes and provides the means for localized protein synthesis in a variety of cell types. Here, we show that hexose transporter mRNAs are retained in the mother cell of S. cerevisiae until metaphase–anaphase transition (MAT) and then are released into the bud. The retained mRNA was translationally less active but bound to ribosomes before MAT. Importantly, when cells were shifted from starvation to glucose-rich conditions, HXT2 mRNA, but none of the other HXT mRNAs, was enriched in the bud after MAT. This enrichment was dependent on the ...
Source: EMBO Journal - May 14, 2019 Category: Molecular Biology Authors: Stahl, T., Hümmer, S., Ehrenfeuchter, N., Mittal, N., Fucile, G., Spang, A. Tags: Cell Cycle, Membrane & Intracellular Transport, Metabolism Articles Source Type: research
YY1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells
Skeletal muscle satellite cells (SCs) are adult muscle stem cells responsible for muscle regeneration after acute or chronic injuries. The lineage progression of quiescent SC toward activation, proliferation, and differentiation during the regeneration is orchestrated by cascades of transcription factors (TFs). Here, we elucidate the function of TF Yin Yang1 (YY1) in muscle regeneration. Muscle-specific deletion of YY1 in embryonic muscle progenitors leads to severe deformity of diaphragm muscle formation, thus neonatal death. Inducible deletion of YY1 in SC almost completely blocks the acute damage-induced muscle repair a...
Source: EMBO Journal - May 14, 2019 Category: Molecular Biology Authors: Chen, F., Zhou, J., Li, Y., Zhao, Y., Yuan, J., Cao, Y., Wang, L., Zhang, Z., Zhang, B., Wang, C. C., Cheung, T. H., Wu, Z., Wong, C. C.-L., Sun, H., Wang, H. Tags: Metabolism, Stem Cells, Transcription Articles Source Type: research
Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza
The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degra...
Source: EMBO Journal - May 14, 2019 Category: Molecular Biology Authors: Park, E.-S., Byun, Y. H., Park, S., Jang, Y. H., Han, W.-R., Won, J., Cho, K. C., Kim, D. H., Lee, A. R., Shin, G.-C., Park, Y. K., Kang, H. S., Sim, H., Ha, Y. N., Jae, B., Son, A., Kim, P., Yu, J., Lee, H.-M., Kwon, S.-B., Kim, K. P., Lee, S.-H., Park, Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Regulation of death receptor signaling by the autophagy protein TP53INP2
TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in death-receptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor-induced apoptosis. TP53INP2 binds caspase-8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspase-8 by TRAF6. We have defined a TRAF6-interacting motif (TIM) and a ubiquitin-interacting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquit...
Source: EMBO Journal - May 14, 2019 Category: Molecular Biology Authors: Ivanova, S., Polajnar, M., Narbona-Perez, A. J., Hernandez-Alvarez, M. I., Frager, P., Slobodnyuk, K., Plana, N., Nebreda, A. R., Palacin, M., Gomis, R. R., Behrends, C., Zorzano, A. Tags: Cancer, Autophagy & Cell Death Articles Source Type: research
Lining up for quality control: linear ubiquitin and proteotoxicity
The post-translational modification of proteins with linear ubiquitin (Ub) has previously been shown to be important for regulating inflammatory and immunological signaling in response to cellular pathogens. However, other functions of linear Ub are currently poorly defined. In this issue of The EMBO Journal, van Well and colleagues define a new role for linear Ub in regulating the intracellular stability and proteotoxicity of protein aggregates implicated in neurodegenerative diseases. This work provides new insights into the pathologic and potential therapeutic implications for linear Ub in the pathogenesis of these diso...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Wiseman, R. L. Tags: Neuroscience, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research
A choreography of intracellular Ca2+ and extracellular ATP to refine auditory nociceptors before hearing
Our hearing ability is exquisite in terms of sensitivity, dynamic range, and frequency discrimination. However, this acuity comes at the price of high vulnerability to a range of adverse influences—including sustained loud sounds. One may therefore expect that the ear is equipped with an alert system that can help prevent hearing damage, akin to the nociceptive sensory system that safeguards us from undergoing tissue injury. Here, Ceriani et al reveal a complex signaling interplay of sensory and non-sensory cells that helps setting up such a system in development. (Source: EMBO Journal)
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Leitner, M. G., Oliver, D. Tags: Development & Differentiation, Membrane & Intracellular Transport News [amp ] Views Source Type: research
The assembly of lipid droplets and their roles in challenged cells
(Source: EMBO Journal)
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Henne, W. M., Reese, M. L., Goodman, J. M. Tags: Corrigendum Source Type: research
A supporting ecosystem to mature extracellular vesicles into clinical application
Research into extracellular vesicles (EV) has yielded important biological insights and raised the prospect of developing novel diagnostics and therapeutics for a wide range of pathologies. As with other emerging and transformative fields in research, it will require a broad, supportive base for EV research to mature and to develop clinical application. Here, we identify several focus areas to further improve reproducibility and reliability specifically for EV research and make recommendations for minimal experimental guidelines, transparency tools, reference materials, validation, identification of contaminants, data shar...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: De Wever, O., Hendrix, A. Tags: Membrane & Intracellular Transport Commentary Source Type: research
Binding of IFT22 to the intraflagellar transport complex is essential for flagellum assembly
Intraflagellar transport (IFT) relies on motor proteins and the IFT complex to construct cilia and flagella. The IFT complex subunit IFT22/RabL5 has sequence similarity with small GTPases although the nucleotide specificity is unclear because of non-conserved G4/G5 motifs. We show that IFT22 specifically associates with G-nucleotides and present crystal structures of IFT22 in complex with GDP, GTP, and with IFT74/81. Our structural analysis unravels an unusual GTP/GDP-binding mode of IFT22 bypassing the classical G4 motif. The GTPase switch regions of IFT22 become ordered upon complex formation with IFT74/81 and mediate mo...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Wachter, S., Jung, J., Shafiq, S., Basquin, J., Fort, C., Bastin, P., Lorentzen, E. Tags: Cell Adhesion, Polarity & Cytoskeleton, Membrane & Intracellular Transport, Structural Biology Articles Source Type: research
A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes
The rate of RNA polymerase II (RNAPII) elongation has an important role in the control of alternative splicing (AS); however, the in vivo consequences of an altered elongation rate are unknown. Here, we generated mouse embryonic stem cells (ESCs) knocked in for a slow elongating form of RNAPII. We show that a reduced transcriptional elongation rate results in early embryonic lethality in mice. Focusing on neuronal differentiation as a model, we observed that slow elongation impairs development of the neural lineage from ESCs, which is accompanied by changes in AS and in gene expression along this pathway. In particula...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Maslon, M. M., Braunschweig, U., Aitken, S., Mann, A. R., Kilanowski, F., Hunter, C. J., Blencowe, B. J., Kornblihtt, A. R., Adams, I. R., Caceres, J. F. Tags: RNA Biology, Transcription Articles Source Type: research
Protein translocation by the SecA ATPase occurs by a power-stroke mechanism
SecA belongs to the large class of ATPases that use the energy of ATP hydrolysis to perform mechanical work resulting in protein translocation across membranes, protein degradation, and unfolding. SecA translocates polypeptides through the SecY membrane channel during protein secretion in bacteria, but how it achieves directed peptide movement is unclear. Here, we use single-molecule FRET to derive a model that couples ATP hydrolysis-dependent conformational changes of SecA with protein translocation. Upon ATP binding, the two-helix finger of SecA moves toward the SecY channel, pushing a segment of the polypeptide into the...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Catipovic, M. A., Bauer, B. W., Loparo, J. J., Rapoport, T. A. Tags: Membrane & Intracellular Transport Articles Source Type: research
A protein quality control pathway regulated by linear ubiquitination
Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unw...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: van Well, E. M., Bader, V., Patra, M., Sanchez-Vicente, A., Meschede, J., Furthmann, N., Schnack, C., Blusch, A., Longworth, J., Petrasch-Parwez, E., Mori, K., Arzberger, T., Trümbach, D., Angersbach, L., Showkat, C., Sehr, D. A., Berlemann, L. A. Tags: Neuroscience, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Intrinsic lipid binding activity of ATG16L1 supports efficient membrane anchoring and autophagy
In this study, we dissected the recruitment of ATG16L1 to the pre-autophagosomal structure (PAS) and showed that it requires sequences within its coiled-coil domain (CCD) dispensable for homodimerisation. Structural and mutational analyses identified conserved residues within the CCD of ATG16L1 that mediate direct binding to phosphoinositides, including phosphatidylinositol 3-phosphate (PI3P). Mutating putative lipid binding residues abrogated the localisation of ATG16L1 to the PAS and inhibited LC3 lipidation. On the other hand, enhancing lipid binding of ATG16L1 by mutating negatively charged residues adjacent to the lip...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Dudley, L. J., Cabodevilla, A. G., Makar, A. N., Sztacho, M., Michelberger, T., Marsh, J. A., Houston, D. R., Martens, S., Jiang, X., Gammoh, N. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research
Mutant Lef1 controls Gata6 in sebaceous gland development and cancer
Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutan...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Oules, B., Rognoni, E., Hoste, E., Goss, G., Fiehler, R., Natsuga, K., Quist, S., Mentink, R., Donati, G., Watt, F. M. Tags: Cancer, Development & Differentiation, Transcription Articles Source Type: research
ALYREF links 3'-end processing to nuclear export of non-polyadenylated mRNAs
The RNA-binding protein ALYREF plays key roles in nuclear export and also 3'-end processing of polyadenylated mRNAs, but whether such regulation also extends to non-polyadenylated RNAs is unknown. Replication-dependent (RD)-histone mRNAs are not polyadenylated, but instead end in a stem-loop (SL) structure. Here, we demonstrate that ALYREF prevalently binds a region next to the SL on RD-histone mRNAs. SL-binding protein (SLBP) directly interacts with ALYREF and promotes its recruitment. ALYREF promotes histone pre-mRNA 3'-end processing by facilitating U7-snRNP recruitment through physical interaction with the U7-snRNP-spe...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Fan, J., Wang, K., Du, X., Wang, J., Chen, S., Wang, Y., Shi, M., Zhang, L., Wu, X., Zheng, D., Wang, C., Wang, L., Tian, B., Li, G., Zhou, Y., Cheng, H. Tags: RNA Biology Articles Source Type: research
