Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas and Centro de Investigación Biomédica en Red de Enfermedades Raras, 46010 Valencia, Spain.
Mol Biol Cell. 2010 Aug 1;21(15):2578-88. doi: 10.1091/mbc.e10-03-0227. Epub 2010 Jun 9.
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.
拉佛拉病是一种进行性肌阵挛癫痫，是由至少两种蛋白功能缺陷引起的致命神经退行性疾病：laforin，一种双特异性蛋白磷酸酶，和 malin，一种 E3 泛素连接酶。在这项研究中，我们报告说，功能性 laforin-malin 复合物促进 AMP 激活的蛋白激酶 (AMPK) 的泛素化，AMPK 是一种丝氨酸/苏氨酸蛋白激酶，作为细胞能量状态的传感器。当细胞中单独表达 AMPK 的三个亚基（alpha、beta 和 gamma）中的任何一个时，都会发生这种反应，当它是异三聚体复合物的一部分时，它也会发生在 AMPK beta 上。我们还报告说，laforin-malin 复合物促进 K63 连接的泛素链的形成，这些泛素链不参与蛋白酶体降解。相反，这种修饰增加了至少 AMPK beta 亚基的稳态水平，可能是因为它导致这种蛋白积累到包涵体中。这些结果表明，laforin-malin 复合物引入的修饰可能会影响 AMPK beta 亚基的亚细胞分布。
