title: Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex.
abstract: Protein phosphatase type 1 (PP1) plays a major role in the regulation of glycogen biosynthesis. PP1 is recruited to sites of glycogen formation by its binding to specific targeting subunits. There, it dephosphorylates different enzymes involved in glycogen homeostasis leading to an activation of glycogen biosynthesis. Regulation of these targeting subunits is crucial, as excess of them leads to an enhancement of the action of PP1, which results in glycogen accumulation. In this work we present evidence that PPP1R3D (R6), one of the PP1 glycogenic targeting subunits, interacts physically with laforin, a glucan phosphatase involved in Lafora disease, a fatal type of progressive myoclonus epilepsy. Binding of R6 to laforin allows the ubiquitination of R6 by the E3-ubiquitin ligase malin, what targets R6 for autophagic degradation. As a result of the action of the laforin-malin complex on R6, its glycogenic activity is downregulated. Since R6 is expressed in brain, our results suggest that the laforin-malin complex downregulates the glycogenic activity of R6 present in neuron cells to prevent glycogen accumulation.
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC, and Centro de Investigación en Red de Enfermedades Raras, Jaime Roig 11, 46010 Valencia, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Rubio-Villena
authors.forename: Maria Adelaida
authors.initials: MA
authors.lastname: Garcia-Gimeno
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
mesh_terms: D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020192:Lafora Disease / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D006003:Glycogen; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C585576:PPP1R3D protein, human; D054645:Protein Phosphatase 1; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor