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J. Biol. Chem., Vol. 283, Issue 7, 4069-4076, February 15, 2008

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Malin Decreases Glycogen Accumulation by Promoting the Degradation of Protein Targeting to Glycogen (PTG)^*

Carolyn A. Worby¹, Matthew S. Gentry¹, and Jack E. Dixon²

From the Departments of Pharmacology, Cellular and Molecular Medicine, and Chemistry and Biochemistry and The Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0721

Lafora disease (LD) is an autosomal recessive neurodegenerative disease that results in progressive myoclonus epilepsy and death. LD is caused by mutations in either the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin. A hallmark of LD is the accumulation of insoluble glycogen in the cytoplasm of cells from most tissues. Glycogen metabolism is regulated by phosphorylation of key metabolic enzymes. One regulator of this phosphorylation is protein targeting to glycogen (PTG/R5), a scaffold protein that binds both glycogen and many of the enzymes involved in glycogen synthesis, including protein phosphatase 1 (PP1), glycogen synthase, phosphorylase, and laforin. Overexpression of PTG markedly increases glycogen accumulation, and decreased PTG expression decreases glycogen stores. To investigate if malin and laforin play a role in glycogen metabolism, we overexpressed PTG, malin, and laforin in tissue culture cells. We found that expression of malin or laforin decreased PTG-stimulated glycogen accumulation by 25%, and co-expression of malin and laforin abolished PTG-stimulated glycogen accumulation. Consistent with this result, we found that malin ubiquitinates PTG in a laforin-dependent manner, both in vivo and in vitro, and targets PTG for proteasome-dependent degradation. These results suggest an additional mechanism, involving laforin and malin, in regulating glycogen metabolism.

Received for publication, October 22, 2007 , and in revised form, December 3, 2007.

^* This work was supported by National Institutes of Health Grants DK018849-33 (to J. E. D.) and 1K99NS061803-01 (to M. S. G.) and the Walther Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: 9500 Gilman Dr., Leichtag Bldg., Rm. 284, La Jolla, CA 92093-0721. Fax: 858-822-5888; E-mail: jedixon{at}ucsd.edu.

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