The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein
| Autor: | Maria Dimitriadi, Anne C. Hart, Casey Cable, Barrington G. Burnett, Ajay B. Chitnis, Barbara Terzic, Kenneth H. Fischbeck, Deborah Y. Kwon |
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| Rok vydání: | 2013 |
| Předmět: |
Ubiquitin-Protein Ligases
animal diseases Blotting Western Hybrid Cells Neuromuscular junction Animals Genetically Modified Mice Neuroblastoma 03 medical and health sciences 0302 clinical medicine Ubiquitin medicine Animals Humans Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology 030304 developmental biology 0303 health sciences biology HEK 293 cells Ubiquitination Survival of motor neuron Articles Cell Biology Spinal muscular atrophy Motor neuron medicine.disease Survival of Motor Neuron 1 Protein Molecular biology nervous system diseases Ubiquitin ligase Cell biology HEK293 Cells medicine.anatomical_structure Spinal Cord nervous system Proteasome Cell Biology of Disease Proteolysis Pharyngeal Muscles biology.protein RNA Interference 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e13-01-0042 |
| Popis: | Spinal muscular atrophy is caused by deficiency of the survival motor neuron (SMN) protein. We show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), ubiquitinates and targets SMN for degradation. Reducing Mib1 increases SMN levels, and decreasing the Caenorhabditis elegans orthologue of Mib1 mitigates a neuromuscular defect characteristic of SMN deficiency. 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. |
| Databáze: | OpenAIRE |
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