PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver.
PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver.
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PHB2 与 LC3 相互作用，SQSTM1 是胆汁酸诱导胆汁淤积性肝脏线粒体自噬所必需的
DOI：
10.1038/s41419-017-0228-8
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Cai W
中科院分区：
文献类型：
--
作者：
Xiao Y;Zhou Y;Lu Y;Zhou K;Cai W
线粒体自噬是清除受损线粒体的主要途径。然而，线粒体自噬是否参与胆汁淤积引起的肝线粒体损伤尚不清楚。我们的目的是研究胆汁淤积和肝线粒体自噬之间的分子联系。我们发现，线粒体自噬是显着增加，在肝脏的胆道闭锁（BA），这是胆汁淤积性疾病的婴儿。胆汁酸的毒性处理增加了肝细胞的线粒体自噬活性。从机制上讲，我们发现，抑制素2（PHB2）是至关重要的胆汁淤积介导的线粒体自噬在体外。一方面，PHB2通过LC3相互作用区域结构域结合损伤线粒体上的自噬体膜相关蛋白LC3。另一方面，PHB2与隔离体1（SQSTM 1）和LC 3形成三元蛋白复合物，导致LC 3加载到受损的线粒体上。总之，我们的研究表明，PHB2是胆汁淤积诱导的线粒体自噬通过LC 3到受损的线粒体上所必需的。
Mitophagy is a major pathway for clearance of injured mitochondria. However, whether mitophagy is involved in the cholestasis-induced damages of hepatic mitochondria remains unknown. We here aimed to investigate the molecular links between cholestasis and hepatic mitophagy. We show that mitophagy is increased significantly in livers of biliary atresia (BA) that is cholestatic disease in infants. The mitochondrial-toxicity bile acids treatment increases the activities of mitophagy in hepatocytes. Mechanistically, we find that the prohibitin 2 (PHB2) is crucial for cholestasis-mediated mitophagy in vitro. On the one hand, PHB2 binds the autophagosomal membrane-associated protein LC3 upon injured mitochondria via an LC3-interaction region domain. On the other hand, PHB2 forms a ternary protein complex with sequestosome 1 (SQSTM1) and LC3, leading to loading of LC3 onto the damaged mitochondria. Altogether, our study suggests that PHB2 is required for cholestasis-induced mitophagy via LC3 onto the injured mitochondria.
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影响因子：
9.3
作者：
Williams JA;Ding WX
通讯作者：
Ding WX
影响因子：
16.6
作者：
Banushi B;Forneris F;Straatman-Iwanowska A;Strange A;Lyne AM;Rogerson C;Burden JJ;Heywood WE;Hanley J;Doykov I;Straatman KR;Smith H;Bem D;Kriston-Vizi J;Ariceta G;Risteli M;Wang C;Ardill RE;Zaniew M;Latka-Grot J;Waddington SN;Howe SJ;Ferraro F;Gjinovci A;Lawrence S;Marsh M;Girolami M;Bozec L;Mills K;Gissen P
通讯作者：
Gissen P
影响因子：
64.5
作者：
Wei Y;Chiang WC;Sumpter R Jr;Mishra P;Levine B
通讯作者：
Levine B
影响因子：
3.8
作者：
Jaeschke, H;Gores, GJ;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
4.8
作者：
Xie, Guoxiang;Zhong, Wei;Jia, Wei
通讯作者：
Jia, Wei