title: Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation.
abstract: Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP), which represses and reversibly regulates the translation of a subset of mRNAs in dendrites. Protein synthesis can be rapidly stimulated by mGluR-induced and protein phosphatase 2a (PP2A)-mediated dephosphorylation of FMRP, which is coupled to the dissociation of FMRP and target mRNAs from miRNA-induced silencing complexes. Here, we report the rapid ubiquitination and ubiquitin proteasome system (UPS)-mediated degradation of FMRP in dendrites upon DHPG (3,5-dihydroxyphenylglycine) stimulation in cultured rat neurons. Using inhibitors to PP2A and FMRP phosphomutants, degradation of FMRP was observed to depend on its prior dephosphorylation. Translational induction of an FMRP target, postsynaptic density-95 mRNA, required both PP2A and UPS. Thus, control of FMRP levels at the synapse by dephosphorylation-induced and UPS-mediated degradation provides a mode to regulate protein synthesis.
authors.affiliation: Department of Cell Biology and Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Vijayalaxmi C
authors.initials: VC
authors.lastname: Nalavadi
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Muddashetty
authors.forename: Christina
authors.initials: C
authors.lastname: Gross
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D029721:Drosophila Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*
chemical_list: D001897:Boronic Acids; D000069286:Bortezomib; D000076122:Disks Large Homolog 4 Protein; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D008565:Membrane Proteins; D008734:Methoxyhydroxyphenylglycol; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D011719:Pyrazines; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D012694:Serine; C501449:Dlg4 protein, rat; C079898:tws protein, Drosophila; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C010117:3,4-dihydroxyphenylglycol