PMID:23615451

Citation	Kwon, DY, Dimitriadi, M, Terzic, B, Cable, C, Hart, AC, Chitnis, A, Fischbeck, KH and Burnett, BG (2013) The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein. Mol. Biol. Cell 24:1863-71
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.
Links	PubMed PMC3681692 Online version:10.1091/mbc.E13-01-0042
Keywords	Animals; Animals, Genetically Modified; Blotting, Western; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans/physiology; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; HEK293 Cells; Humans; Hybrid Cells; Mice; Neuroblastoma/pathology; Pharyngeal Muscles/metabolism; Pharyngeal Muscles/physiopathology; Protein Binding; Proteolysis; RNA Interference; Spinal Cord/cytology; Survival of Motor Neuron 1 Protein/genetics; Survival of Motor Neuron 1 Protein/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MIB1		GO:0006511: ubiquitin-dependent protein catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		The organism is H. Sapiens and the protein is MIB1 (E3 ubiquitin-protein ligase MIB1).. Fig 1C confirms the ubiquitination of SMN by MIB1. Fig 1D: "We found that overexpressing wild-type Mib1 decreased the half-life of newly synthesized radiolabeled SMN by half, from ∼4 to 2 h, compared with the active-site Mib1 mutant." Figure 2A shows that this ubiquitination lowers the half life of SMN by targeting it for proteasomal degradation	complete CACAO 13044

References

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