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Molecular and Cellular Biology, March 2009, p. 1107-1115, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01262-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of SMN Protein Stability{triangledown} ,{dagger}

Barrington G. Burnett,1* Eric Muñoz,1 Animesh Tandon,1 Deborah Y. Kwon,1 Charlotte J. Sumner,2 and Kenneth H. Fischbeck1

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland,1 Department of Neurology, Johns Hopkins University, Baltimore, Maryland2

Received 8 August 2008/ Returned for modification 16 September 2008/ Accepted 8 December 2008

Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMN{Delta}7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMN{Delta}7 proteins have been largely unexplored. Using pulse-chase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMN{Delta}7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.

* Corresponding author. Mailing address: Neurogenetics Branch, NIH, Bldg. 35, Rm. 2A1008, Bethesda, MD 20892. Phone: (301) 435-9288. Fax: (301) 480-3365. E-mail: burnettb{at}ninds.nih.gov

{triangledown} Published ahead of print on 22 December 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2009, p. 1107-1115, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01262-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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