Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2.
Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2.
复制标题
DOI：
10.26508/lsa.202000806
复制
发表时间：
2021-06
影响因子：
4.4
通讯作者：
Tramier M
中科院分区：
文献类型：
--
作者：
Bertolin G;Alves-Guerra MC;Cheron A;Burel A;Prigent C;Le Borgne R;Tramier M
多功能Ser/Thr激酶AURKA利用线粒体内膜受体PHB2和MAP1LC3作为信号平台，协调线粒体功能障碍的消除。上皮性和血液性肿瘤通常表现为丝氨酸/苏氨酸激酶AURKA的过度表达。最近，AURKA被发现定位于线粒体，在那里它调节线粒体的动力学和ATP的产生。在这里，我们定义了AURKA通过有丝分裂调节线粒体周转的分子机制。AURKA通过与自噬途径的核心成分相互作用，触发内线粒体膜/基质蛋白的降解。在线粒体膜上，该激酶与MAP1LC3和吞线体受体PHB2形成三段复合体，以PARK2/Parkin不依赖的方式触发有丝分裂。三方复合体的形成是由Ser39上PHB2的磷酸化诱导的，这是MAP1LC3与PHB2相互作用所必需的。最后，用PHB2配体黄腐酚通过破坏三方复合体的稳定来阻断AURKA诱导的有丝分裂，并恢复正常的ATP生产水平。总之，这些数据为AURKA通过与PHB2和MAP1LC3的相互作用促进有丝分裂的作用提供了证据。这项工作为使用功能特异的药物抑制剂来对抗癌症中AURKA过表达的影响铺平了道路。
The multifunctional Ser/Thr kinase AURKA uses the Inner Mitochondrial Membrane receptor PHB2 and MAP1LC3 as a signalling platform to orchestrate the elimination of dysfunctional mitochondria. Epithelial and haematologic tumours often show the overexpression of the serine/threonine kinase AURKA. Recently, AURKA was shown to localise at mitochondria, where it regulates mitochondrial dynamics and ATP production. Here we define the molecular mechanisms of AURKA in regulating mitochondrial turnover by mitophagy. AURKA triggers the degradation of Inner Mitochondrial Membrane/matrix proteins by interacting with core components of the autophagy pathway. On the inner mitochondrial membrane, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2, which triggers mitophagy in a PARK2/Parkin–independent manner. The formation of the tripartite complex is induced by the phosphorylation of PHB2 on Ser39, which is required for MAP1LC3 to interact with PHB2. Last, treatment with the PHB2 ligand xanthohumol blocks AURKA-induced mitophagy by destabilising the tripartite complex and restores normal ATP production levels. Altogether, these data provide evidence for a role of AURKA in promoting mitophagy through the interaction with PHB2 and MAP1LC3. This work paves the way to the use of function-specific pharmacological inhibitors to counteract the effects of the overexpression of AURKA in cancer.