DYNAMIC REGULATION OF THE MAINTENANCE AND FUNCTION OF NEURAL CELLS BY THE UBIOUITIN SYSTEM

我们之前发现泛素c端水解酶Ll （UCH-L1）是细轴突营养不良（gad）表型的负责基因产物（Nature Genetics, 1999）。UCH-L1是去泛素化酶家族的成员，在神经元中选择性表达。缺乏UCH-L1表达的小鼠在病理上表现为轴突变性的死回型。在本研究中，我们旨在阐明去泛素化酶对神经细胞维持和功能的可能动态调节机制。我们最初发现UCH-L1意外地结合并稳定神经元中的单泛素。UCH-L1的这种新活性与它的水解酶活性无关。我们随后发现UCH-Li的这种新活性参与调节P2X型ATP受体的活性和神经祖细胞的形态。我们进一步发现UCH-L3， UCH-L1的相关分子，参与细胞凋亡。在uch - l3缺陷小鼠的视网膜中，当视网膜细胞受到损伤时，caspase不依赖性凋亡增加。UCH-L3在细胞凋亡中可能与UCH-L1有相反的作用。综上所述，我们认为去泛素化酶可能以多种方式发挥其生物活性

We previously identified that ubiquitin C-terminal hydrolase Ll (UCH-L1) is the responsible gene product for the gracile axonal dystrophy (gad) phenotype (Nature Genetics, 1999). UCH-L1 is a member of the deubiquitinating enzyme family and is selectively expressed in neurons. The gad mouse that lacks the expression of UCH-L1 is pathologically characterized by dying-back type of axonal degeneration. In this study, we aimed to elucidate the mechanism of a possible dynamic regulation of the maintenance and function of neural cells by deubiquitinating enzymes. We initially showed that UCH-L1 unexpectedly binds to and stabilizes monoubiquitin in neurons. This novel activity of UCH-L1 is independent on its hydrolase activity. We subsequently identified that this novel activity of UCH-Li is involved in the regulation of the activity of P2X type of ATP receptors and the morphology of neural progenitor cells. We further identified that UCH-L3, a related molecule to UCH-L1, is involved in cell apoptosis. In the retina of UCH-L3-deficient mice, caspase-independent apoptosis increased when retinal cells were insulted. UCH-L3 may have an opposing role against UCH-L1 in the cell apoptosis. In summary, we indicate that deubiquitinating enzymes may exert their biological activities in multiple ways