Division of Gastrointestinal and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California, Los Angeles, California 90089-9121, USA.
J Biol Chem. 2011 Oct 7;286(40):35071-8. doi: 10.1074/jbc.M111.276089. Epub 2011 Aug 15.
Sustained JNK activation plays a critical role in hepatotoxicity by acetaminophen or GalN/TNF-α. To address the importance of JNK translocation to mitochondria that accompanies sustained activation in these models, we assessed the importance of the expression of a potential initial target of JNK in the outer membrane of mitochondria, namely Sab (SH3 domain-binding protein that preferentially associates with Btk), also known as Sh3bp5 (SH3 domain-binding protein 5). Silencing the expression of Sab in the liver using adenoviral shRNA inhibited sustained JNK activation and mitochondrial targeting of JNK and the upstream MKK4 (MAPK kinase 4), accompanied by striking protection against liver injury in vivo and in cultured hepatocytes in both toxicity models. We conclude that mitochondrial Sab may serve as a platform for the MAPK pathway enzymes and that the interaction of stress-activated JNK with Sab is required for sustained JNK activation and toxicity.
持续的 JNK 激活在对乙酰氨基酚或 GalN/TNF-α的肝毒性中起着关键作用。为了研究在这些模型中伴随着持续激活的 JNK 向线粒体易位的重要性，我们评估了 JNK 在位于外膜上的一个潜在初始靶标（即 Sab，也称为 Sh3bp5）的表达的重要性，Sab 是一种 SH3 结构域结合蛋白，优先与 Btk 结合）。使用腺病毒 shRNA 沉默肝脏中 Sab 的表达可抑制 JNK 的持续激活和 JNK 向线粒体的靶向以及上游 MKK4（MAPK 激酶 4），从而在体内和两种毒性模型的培养肝细胞中对肝损伤产生显著的保护作用。我们得出结论，线粒体 Sab 可能作为 MAPK 途径酶的平台，应激激活的 JNK 与 Sab 的相互作用对于持续的 JNK 激活和毒性是必需的。
