Phosphorylated hamartin-Hsp70 complex regulates apoptosis via mitochondrial localization
Phosphorylated hamartin-Hsp70 complex regulates apoptosis via mitochondrial localization
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DOI：
10.1016/j.bbrc.2009.12.054
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发表时间：
2010-01-01
影响因子：
3.1
通讯作者：
Yamamoto, Yuji
中科院分区：
文献类型：
--
作者：
Inoue, Hirofumi;Uyama, Takumi;Yamamoto, Yuji
结节性硬化症复合体 (TSC) 基因的产物错构蛋白和马铃薯蛋白形成异二聚体。最近我们报道了 Hamartin 直接与 Hsp70 相互作用。然而，这种相互作用的生理学意义尚未明确定义。在这里，我们证明错构蛋白以 Hsp70 依赖性方式定位于线粒体外膜。此外，错构蛋白 T417 残基的磷酸化是其定位到线粒体以及与 Hsp70 相互作用所必需的。残基 T417 处的不可磷酸化错构蛋白突变体无法定位于线粒体并抑制细胞凋亡，而不可磷酸化错构蛋白突变体 T357A 和 T390A 定位于线粒体并抑制细胞凋亡。重要的是，非磷酸化突变体（T357A、T390A 和 T417A）在用 Hsp 70 抑制剂 KNK437 处理后促进细胞凋亡。我们得出结论，错构蛋白通过定位于线粒体来抑制细胞凋亡，并且其磷酸化和与 Hsp70 的结合是促进这一过程所必需的。 (C) 2009 Elsevier Inc. 保留所有权利。
The products of the tuberous sclerosis complex (TSC) genes, hamartin and tuberin, form a heterodimer. Recently we reported that hamartin directly interacted with Hsp70. However, the physiological implications of this interaction have not yet been clearly defined. Here we show that hamartin localized to the outer membrane of the mitochondria in an Hsp70-dependent manner. Moreover, phosphorylation of the T417 residue of hamartin was required for its localization to the mitochondria as well as its interaction with Hsp70. A non-phosphorylatable hamartin mutant at residue T417 was unable to localize to the mitochondria and suppress apoptosis, whereas non-phosphorylatable hamartin mutants T357A and T390A localized to the mitochondria and suppressed apoptosis. Importantly, non-phosphorylatable mutants (T357A, T390A and T417A) promoted apoptosis after treatment with Hsp 70-inhibitor KNK437. We conclude that hamartin inhibited apoptosis by localizing to the mitochondria and that its phosphorylation and binding to Hsp70 was required for facilitation of this process. (C) 2009 Elsevier Inc. All rights reserved.