c-Jun N-末端激酶通过一种新的 Sab (SH3BP5) 依赖性通路介导小鼠肝损伤，导致线粒体内 Src 失活,Hepatology

当前位置： X-MOL 学术 › Hepatology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

c-Jun N-末端激酶通过一种新的 Sab (SH3BP5) 依赖性通路介导小鼠肝损伤，导致线粒体内 Src 失活
Hepatology ( IF 12.9 ) Pub Date : 2016-03-15 , DOI: 10.1002/hep.28486
Sanda Win ₁ , Tin Aung Than ₁ , Robert Win Maw Min ₁ , Mariam Aghajan ₂ , Neil Kaplowitz ₁

Affiliation

持续的 c-Jun N 末端激酶 (JNK) 激活与许多细胞死亡和组织损伤模型有关。磷酸化 JNK (p-JNK) 与线粒体外膜 SH3 同源相关的 BTK 结合蛋白（Sab 或 SH3BP5）相互作用。使用敲除或肝脏特异性 Sab 缺失，我们旨在阐明这种相互作用对体内分离线粒体和肝损伤模型中线粒体功能的影响。p-JNK + 三磷酸腺苷直接抑制分离线粒体的呼吸。Sab 的敲低或肝脏特异性敲除消除了这种作用，并显着抑制了对乙酰氨基酚或肿瘤坏死因子/半乳糖胺的持续 JNK 激活和肝损伤。然后我们阐明了一种线粒体内途径，其中线粒体外部的 JNK 和 Sab 的相互作用从线粒体外膜内部的 Sab 释放蛋白质酪氨酸磷酸酶，非受体 6 型（SHP1 或 PTPN6），导致其激活和转移到内膜，在那里它使 P-Y419Src（活性）去磷酸化，这需要在内膜上的平台蛋白，对接蛋白 4（DOK4）。线粒体 DOK4 或 SHP1 的敲低抑制了线粒体 p-Src 的失活和 p-JNK 对线粒体的影响。结论：线粒体外膜上 p-JNK 对 Sab 的结合和磷酸化导致内膜上 p-Src 的 SHP1 依赖性和 DOK4 依赖性失活；线粒体 Src 的失活会抑制电子传递并增加活性氧的释放，从而维持 JNK 活化并促进细胞死亡和器官损伤。（肝病学 2016；63：1987-2003）

"点击查看英文标题和摘要"

c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src

Sustained c‐Jun N‐terminal kinase (JNK) activation has been implicated in many models of cell death and tissue injury. Phosphorylated JNK (p‐JNK) interacts with the mitochondrial outer membrane SH3 homology associated BTK binding protein (Sab, or SH3BP5). Using knockdown or liver‐specific deletion of Sab, we aimed to elucidate the consequences of this interaction on mitochondrial function in isolated mitochondria and liver injury models in vivo. Respiration in isolated mitochondria was directly inhibited by p‐JNK + adenosine triphosphate. Knockdown or liver‐specific knockout of Sab abrogated this effect and markedly inhibited sustained JNK activation and liver injury from acetaminophen or tumor necrosis factor/galactosamine. We then elucidated an intramitochondrial pathway in which interaction of JNK and Sab on the outside of the mitochondria released protein tyrosine phosphatase, nonreceptor type 6 (SHP1, or PTPN6) from Sab in the inside of the mitochondrial outer membrane, leading to its activation and transfer to the inner membrane, where it dephosphorylates P‐Y419Src (active), which required a platform protein, docking protein 4 (DOK4), on the inner membrane. Knockdown of mitochondrial DOK4 or SHP1 inhibited the inactivation of mitochondrial p‐Src and the effect of p‐JNK on mitochondria. Conclusions: The binding to and phosphorylation of Sab by p‐JNK on the outer mitochondrial membrane leads to SHP1‐dependent and DOK4‐dependent inactivation of p‐Src on the inner membrane; inactivation of mitochondrial Src inhibits electron transport and increases reactive oxygen species release, which sustains JNK activation and promotes cell death and organ injury. (Hepatology 2016;63:1987‐2003)

更新日期：2016-03-15

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南