title: The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein.
abstract: Spinal muscular atrophy is an inherited motor neuron disease that results from a deficiency of the survival of motor neuron (SMN) protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition increases SMN protein levels, improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy (SMA) mice. Specific targets in the UPS may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. Also, knocking down the Mib1 orthologue improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for SMA.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Deborah Y
authors.initials: DY
authors.lastname: Kwon
authors.forename: Maria
authors.initials: M
authors.lastname: Dimitriadi
authors.forename: Barbara
authors.initials: B
authors.lastname: Terzic
authors.forename: Casey
authors.initials: C
authors.lastname: Cable
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
authors.forename: Ajay
authors.initials: A
authors.lastname: Chitnis
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D010609:Pharyngeal Muscles / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D013116:Spinal Cord / Q000166:cytology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D029742:Caenorhabditis elegans Proteins; D055533:Survival of Motor Neuron 1 Protein; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; C585645:mib-1 protein, C elegans