title: Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation.
abstract: Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblasts, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K-mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex.
authors.affiliation: Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: ilbecker@iib.uam.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.affiliation: Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Nonis
authors.affiliation: Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Eich
authors.affiliation: Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Center of Excellence Macromolecular Complexes, Institute of Molecular Biosciences, Goethe-University, 60590 Frankfurt am Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kötter
authors.affiliation: Translational Medicine and Neurogenetics Department, Institut de Génétique et Biologie Moléculaire et Cellulaire, UMR7104-CNRS/U964-INSERM/UDS, BP10142, 67404 Illkirch Cédex, France.
authors.forename: Fabrice A C
authors.initials: FA
authors.lastname: Klein
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kedersha
authors.affiliation: Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: auburger@em.uni-frankfurt.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity; D000067698:Ataxin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013217:Starvation / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018053:Arsenites; D000067698:Ataxin-2; D039642:Eukaryotic Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D058570:TOR Serine-Threonine Kinases; C015001:arsenite
keywords: Amyotrophic lateral sclerosis; Diabetes mellitus; Spinocerebellar Ataxia type 2; TORC1; mRNA translation