Habelhah Hasem, Laine Aaron, Erdjument-Bromage Hediye, Tempst Paul, Gershwin M Eric, Bowtell David D L, Ronai Ze'ev
Department of Oncological Sciences, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
J Biol Chem. 2004 Dec 17;279(51):53782-8. doi: 10.1074/jbc.M410315200. Epub 2004 Oct 5.
The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the alpha-ketoglutarate dehydrogenase complex) is a rate-limiting enzyme in the mitochondrial Krebs cycle. Here we report that the RING finger ubiquitin-protein isopeptide ligase Siah2 binds to and targets OGDHC-E2 for ubiquitination-dependent degradation. OGDHC-E2 expression and activity are elevated in Siah2(-/-) cells compared with Siah2(+)(/)(+) cells. Deletion of the mitochondrial targeting sequence of OGDHC-E2 results in its cytoplasmic localization and rapid proteasome-dependent degradation in Siah2(+)(/)(+) but not in Siah2(-/-) cells. Significantly, because of its overexpression or disruption of the mitochondrial membrane potential, the release of OGDHC-E2 from mitochondria to the cytoplasm also results in its concomitant degradation. The role of the Siah family of ligases in the regulation of OGDHC-E2 stability is expected to take place under pathological conditions in which the levels of OGDHC-E2 are altered.
2-氧代戊二酸脱氢酶复合体（OGHDC）（也称为α-酮戊二酸脱氢酶复合体）是线粒体三羧酸循环中的一种限速酶。在此我们报告，环状泛素蛋白异肽连接酶Siah2与OGDHC-E2结合并使其成为泛素化依赖性降解的靶点。与Siah2(+)(/)(+)细胞相比，OGDHC-E2的表达和活性在Siah2(-/-)细胞中升高。删除OGDHC-E2的线粒体靶向序列会导致其定位于细胞质，并在Siah2(+)(/)(+)细胞中依赖蛋白酶体快速降解，而在Siah2(-/-)细胞中则不会。值得注意的是，由于其过表达或线粒体膜电位的破坏，OGDHC-E2从线粒体释放到细胞质中也会导致其随之降解。预计连接酶Siah家族在调节OGDHC-E2稳定性中的作用将在OGDHC-E2水平发生改变的病理条件下发挥。
