Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron*
- Ke-Jun Han‡,
- Daniel G. Foster‡,
- Nan-Yan Zhang‡,1,
- Kavdia Kanisha§,
- Monika Dzieciatkowska‡,
- Robert A. Sclafani‡,
- Kirk C. Hansen‡,
- Junmin Peng§ and
- Chang-Wei Liu‡,2
- From the ‡Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045 and
- the §Structural Biology and Developmental Neurobiology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee 38105
- ↵2 To whom correspondence should be addressed. E-mail: changwei.liu{at}ucdenver.edu.
Abstract
Spinal muscular atrophy (SMA), the leading genetic disorder of infant mortality, is caused by low levels of survival motor neuron (SMN) protein. Currently it is not clear how the SMN protein levels are regulated at the post-transcriptional level. In this report, we find that Usp9x, a deubiquitinating enzyme, stably associates with the SMN complex via directly interacting with SMN. Usp9x deubiquitinates SMN that is mostly mono- and di-ubiquitinated. Knockdown of Usp9x promotes SMN degradation and reduces the protein levels of SMN and the SMN complex in cultured mammalian cells. Interestingly, Usp9x does not deubiquitinate nuclear SMNΔ7, the main protein product of the SMN2 gene, which is polyubiquitinated and rapidly degraded by the proteasome. Together, our results indicate that SMN and SMNΔ7 are differently ubiquitinated; Usp9x plays an important role in stabilizing SMN and the SMN complex, likely via antagonizing Ub-dependent SMN degradation.
- Deubiquitination
- Proteasome
- Protein Degradation
- Ubiquitin-dependent Protease
- Ubiquitination
- Spinal Muscular Atrophy
- Survival Motor neuron
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant 5RO1NS72397 (to C. W. L.) and grants from the American-Syrian-Lebanese Associated Charities (to J. P.) and the Cancer League of Colorado (to K. J. H.).
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This article contains supplemental Figs. S1–S8.
- Received April 16, 2012.
- Revision received October 22, 2012.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
