title: The deubiquitinating enzyme USP-46 negatively regulates the degradation of glutamate receptors to control their abundance in the ventral nerve cord of Caenorhabditis elegans.
abstract: Ubiquitin-mediated endocytosis and post-endocytic trafficking of glutamate receptors control their synaptic abundance and are implicated in modulating synaptic strength. Ubiquitination is a reversible modification, but the identities and specific functions of deubiquitinating enzymes in the nervous system are lacking. Here, we show that the deubiquitinating enzyme ubiquitin-specific protease-46 (USP-46) regulates the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans. Mutants lacking usp-46 have decreased GLR-1 in the ventral nerve cord and corresponding defects in GLR-1-dependent behaviors. The amount of ubiquitinated GLR-1 is increased in usp-46 mutants. Mutations that block GLR-1 ubiquitination or receptor degradation in the multi-vesicular body/lysosome prevent the decrease in GLR-1 observed in usp-46 mutants. These data support a model in which USP-46 promotes GLR-1 abundance at synapses by deubiquitinating GLR-1 and preventing its degradation in the lysosome. This work suggests that the balance between the addition and removal of ubiquitin is important for glutamate receptor trafficking.
authors.affiliation: Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Kowalski
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Dahlberg
authors.forename: Peter
authors.initials: P
authors.lastname: Juo
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D057146:Multivesicular Bodies / Q000378:metabolism; D009154:Mutation; D009420:Nervous System / Q000378:metabolism*; D021381:Protein Transport; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D015415:Biomarkers; D029742:Caenorhabditis elegans Proteins; D018091:Receptors, AMPA; C096470:glr-1 protein, C elegans; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases