The Laforin-Malin Complex, Involved in Lafora Disease, Promotes the Incorporation of K63-linked Ubiquitin Chains into AMP-activated Protein Kinase beta Subunits

TY - JOUR

T1 - The Laforin-Malin Complex, Involved in Lafora Disease, Promotes the Incorporation of K63-linked Ubiquitin Chains into AMP-activated Protein Kinase beta Subunits

AU - Moreno, Daniel

AU - Towler, Mhairi C.

AU - Hardie, D. Grahame

AU - Knecht, Erwin

AU - Sanz, Pascual

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Lafora progressive myoclonus epilepsy is a fatal neurodegenerative disorder caused by defects in the function of at least two proteins: laforin, a dual-specificity protein phosphatase, and malin, an E3-ubiquitin ligase. In this study, we report that a functional laforin-malin complex promotes the ubiquitination of AMP-activated protein kinase (AMPK), a serine/threonine protein kinase that acts as a sensor of cellular energy status. This reaction occurs when any of the three AMPK subunits (alpha, beta, and gamma) are expressed individually in the cell, and it also occurs on AMPK beta when it is part of a heterotrimeric complex. We also report that the laforin-malin complex promotes the formation of K63-linked ubiquitin chains, which are not involved in proteasome degradation. On the contrary, this modification increases the steady-state levels of at least AMPK beta subunit, possibly because it leads to the accumulation of this protein into inclusion bodies. These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.

AB - Lafora progressive myoclonus epilepsy is a fatal neurodegenerative disorder caused by defects in the function of at least two proteins: laforin, a dual-specificity protein phosphatase, and malin, an E3-ubiquitin ligase. In this study, we report that a functional laforin-malin complex promotes the ubiquitination of AMP-activated protein kinase (AMPK), a serine/threonine protein kinase that acts as a sensor of cellular energy status. This reaction occurs when any of the three AMPK subunits (alpha, beta, and gamma) are expressed individually in the cell, and it also occurs on AMPK beta when it is part of a heterotrimeric complex. We also report that the laforin-malin complex promotes the formation of K63-linked ubiquitin chains, which are not involved in proteasome degradation. On the contrary, this modification increases the steady-state levels of at least AMPK beta subunit, possibly because it leads to the accumulation of this protein into inclusion bodies. These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.

KW - PROGRESSIVE MYOCLONUS EPILEPSY

KW - CONJUGATING ENZYMES

KW - PHOSPHATASE LAFORIN

KW - RETICULUM STRESS

KW - GLYCOGEN

KW - DEGRADATION

KW - BINDING

KW - MUTATIONS

KW - GENE

KW - POLYUBIQUITINATION

U2 - 10.1091/mbc.E10-03-0227

DO - 10.1091/mbc.E10-03-0227

M3 - Article

C2 - 20534808

SN - 1059-1524

VL - 21

SP - 2578

EP - 2588

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

IS - 15

ER -