SUMOylation substrates in neuronal intranuclear inclusion disease
SUMOylation substrates in neuronal intranuclear inclusion disease
复制标题
DOI：
10.1111/j.1365-2990.2005.00705.x
复制
发表时间：
2006-02-01
影响因子：
5
通讯作者：
Fujigasaki, H
中科院分区：
文献类型：
--
作者：
Takahashi-Fujigasaki, J;Arai, K;Fujigasaki, H
神经元核内包涵体病（NIID）是一种罕见的神经退行性疾病，其病理特征是神经元细胞内存在泛素化的核内包涵体（NII）。我们证明，NIIs在散发性和家族性NIID包含小泛素修饰剂-1（SUMO-1）和SUMO化底物早幼粒细胞白血病蛋白（PML）和组蛋白去乙酰化酶4（HDAC 4）。PML和SUMO-1都是核小体（NB）的主要组成部分，这表明NIID中的NII以及多聚谷氨酰胺疾病中的核内包涵体可能来自这些核内功能结构域，这些功能结构域作为泛素相关蛋白降解的位点。HDAC 4也是NII的主要成分。HDAC是调节组蛋白重构的转录辅抑制因子，并且NB被认为是控制组蛋白乙酰化水平的位点。PML、SUMO-1和HDAC 4在NIIs中的存在表明，受组蛋白乙酰化调节的转录活性可能有助于NIID的疾病过程。此外，我们发现另一种SUMO化底物RanGAP 1仅在家族性NIID患者中与NIIs相关。这可能是由于NIID亚类的发病机制不同，这是非常异质性的。
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized pathologically by the presence of ubiquitinated intranuclear inclusions (NII) in neuronal cells. We demonstrate that NIIs in both sporadic and familial NIID contained the small ubiquitin modifier-1 (SUMO-1) and the SUMOylation substrates promyelocytic leukaemia protein (PML) and histone deacetylase 4 (HDAC4). Both PML and SUMO-1 are major components of nuclear bodies (NBs), suggesting that the NIIs in NIID, as well as the intranuclear inclusions in polyglutamine diseases, might derive from these intranuclear functional domains that serve as sites for ubiquitin-related protein degradation. HDAC4 was also a major component of the NIIs. HDACs are transcriptional corepressors that regulate histone remodelling, and NBs are thought to be sites at which the level of histone acetylation is controlled. The presence of PML, SUMO-1 and HDAC4 in NIIs suggests that transcriptional activity regulated by histone acetylation might contribute to the disease process in NIID. In addition, we showed that another SUMOylation substrate, RanGAP1 is associated with NIIs only in the familial NIID patient. This might be explained by different pathogenetic mechanisms underlying subcategories of NIID, which is very heterogeneous.