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A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

¹ Department of Internal Medicine and Department of Physiology, Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA; ² Department of Pharmacology, Department of Cellular and Molecular Medicine, School of Medicine, and Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA

Cori’s disease is a glycogen storage disorder characterized by a deficiency in the glycogen debranching enzyme, amylo-1,6-glucosidase,4--glucanotransferase (AGL). Here, we demonstrate that the G1448R genetic variant of AGL is unable to bind to glycogen and displays decreased stability that is rescued by proteasomal inhibition. AGL G1448R is more highly ubiquitinated than its wild-type counterpart and forms aggresomes upon proteasome impairment. Furthermore, the E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. Malin is known to be mutated in Lafora disease, an autosomal recessive disorder clinically characterized by the accumulation of polyglucosan bodies resembling poorly branched glycogen. Transfection studies in HepG2 cells demonstrate that AGL is cytoplasmic whereas Malin is predominately nuclear. However, after depletion of glycogen stores for 4 h, 90% of transfected cells exhibit partial nuclear staining for AGL. Furthermore, stimulation of cells with agents that elevate cAMP increases Malin levels and Malin/AGL complex formation. Refeeding mice for 2 h after an overnight fast causes a reduction in hepatic AGL levels by 48%. Taken together, these results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori’s disease.

[Keywords: Glycogen debranching enzyme; Lafora disease; Cori’s disease; ubiquitination; Malin]

Received March 19, 2007; revised version accepted August 15, 2007.

E-MAIL saltiel{at}lsi.umich.edu; FAX (734) 763-6492.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1553207

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