The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits.
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.
Moreno
Daniel
D
Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 46010 Valencia, Spain.
Towler
Mhairi C
MC
Hardie
D Grahame
DG
Knecht
Erwin
E
Sanz
Pascual
P
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D020192:Lafora Disease / Q000201:enzymology*; D007976:Leupeptins / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055503:Protein Multimerization / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000187:drug effects
D002352:Carrier Proteins; D007976:Leupeptins; D046912:Multiprotein Complexes; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; C526182:PRKAB1 protein, human; C526183:PRKAB2 protein, human; D055372:AMP-Activated Protein Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human; D046988:Proteasome Endopeptidase Complex; D008239:Lysine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde