Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor γ coactivator 1α
Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor γ coactivator 1α
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DOI：
10.1074/jbc.m703634200
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发表时间：
2007-08-31
影响因子：
4.8
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Sano, Motoaki;Tokudome, Satori;Fukuda, Keiichi
过氧化物酶体增殖物激活受体γ辅激活因子（PGC）-1是能量代谢的关键转录调节因子.在这里，我们发现PGC-1 α是一种寿命短且易于聚集的蛋白质。PGC-1 α定位于整个核质中，并通过泛素-蛋白酶体途径被迅速破坏。在蛋白酶体抑制后，PGC-1 α形成不溶性聚泛素化聚集体。PGC-1 α的泛素化依赖于C末端含有富含丝氨酸的结构域和RNA识别基序的完整性。有趣的是，异位表达的PGC-1 α的C-末端片段被自主泛素化并与早幼粒细胞白血病蛋白聚集。含有两个PEST样基序的N-末端区域的合作是防止聚集和靶向聚泛素化PGC- 1 α降解所必需的。因此，该区域负控制C-末端区域的聚集特性，以调节蛋白质周转和PGC-1 α的核内区室化。PGC-1 α C-末端片段的外源表达干扰全长PGC-1 α的降解并增强其共激活特性。我们的结论是，PGC-1 α的功能在多个步骤中通过蛋白质的几个不同结构域之间的分子内合作受到严格调控。
Peroxisome proliferator- activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1 alpha is a short lived and aggregation-prone protein. PGC-1 alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1 alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1 alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1 alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeting of the polyubiquitinated PGC- 1 alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1 alpha. Exogenous expression of the PGC-1 alpha C-terminal fragment interfered with degradation of full-length PGC-1 alpha and enhanced its coactivation properties. We concluded that PGC-1 alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.