title: Screening of small molecules affecting mammalian P-body assembly uncovers links with diverse intracellular processes and organelle physiology.
abstract: Processing bodies (P-bodies) are cytoplasmatic mRNP granules containing non-translating mRNAs and proteins from the mRNA decay and silencing machineries. The mechanism of P-body assembly has been typically addressed by depleting P-body components. Here we apply a complementary approach and establish an automated cell-based assay platform to screen for molecules affecting P-body assembly. From a unique library of compounds derived from myxobacteria, 30 specifically inhibited P-body assembly. Gephyronic acid A (GA), a eukaryotic protein synthesis inhibitor, showed the strongest effect. GA also inhibited, under stress conditions, phosphorylation of eIF2α and stress granule formation. Other hits uncovered interesting novel links between P-body assembly, lipid metabolism, and internal organelle physiology. The obtained results provide a chemical toolbox to manipulate P-body assembly and function.
authors.affiliation: Infection Biology Group; Department of Experimental and Health Sciences; Universitat Pompeu Fabra; Barcelona, Spain.
authors.forename: Javier P
authors.initials: JP
authors.lastname: Martínez
authors.affiliation: Molecular Virology Group; Department of Experimental and Health Sciences; Universitat Pompeu Fabra; Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pérez-Vilaró
authors.affiliation: Department of Chemical Biology; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Yazh
authors.initials: Y
authors.lastname: Muthukumar
authors.affiliation: Molecular Virology Group; Department of Experimental and Health Sciences; Universitat Pompeu Fabra; Barcelona, Spain.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Scheller
authors.affiliation: Department of Chemical Biology; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Hirsch
authors.affiliation: Department of Chemical Biology; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Randi
authors.initials: R
authors.lastname: Diestel
authors.affiliation: Department of Microbial Drugs; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.affiliation: Department of Microbial Drugs; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Chemical Biology; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.affiliation: Department of Chemical Biology; Helmholtz Centre for Infection Research; Braunschweig, Germany.
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.affiliation: Infection Biology Group; Department of Experimental and Health Sciences; Universitat Pompeu Fabra; Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA); Barcelona, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyerhans
authors.affiliation: Molecular Virology Group; Department of Experimental and Health Sciences; Universitat Pompeu Fabra; Barcelona, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Díez
mesh_terms: D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D055808:Drug Discovery; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D009231:Myxococcales / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011691:Puromycin / Q000494:pharmacology; D020871:RNA Stability; D020736:Ribonucleoproteins, Small Cytoplasmic / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D015852:Eukaryotic Initiation Factor-2; D005229:Fatty Acids, Monounsaturated; D020736:Ribonucleoproteins, Small Cytoplasmic; D054852:Small Molecule Libraries; C092168:gephyronic acid; D011691:Puromycin; D003513:Cycloheximide
keywords: P-body assembly; eIF2α; gephyronic acid A; inhibitors; myxobacterial metabolites; processing bodies; stress granules