Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics
Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics
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DOI：
10.1038/s41467-018-08004-0
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发表时间：
2019-01-10
影响因子：
16.6
通讯作者：
Chen, Junjie
中科院分区：
文献类型：
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作者：
Chen, Zhen;Lei, Caoqi;Chen, Junjie
AMP激活蛋白激酶（AMPK）是细胞能量稳态的关键调节因子。尽管AMPK在细胞过程中已被广泛研究，但对其底物和下游功能网络及其对细胞命运和疾病发展的贡献的理解仍然不完整。为了阐明AMPK依赖的信号通路，我们使用野生型和AMPK α 1/412双敲除细胞进行了全局定量磷酸化蛋白质组学分析，发现了160个AMPK依赖的磷酸化位点。使用AMPK共有磷酸化基序的进一步分析表明，这些位点中的32个可能是直接AMPK磷酸化位点。我们验证了一个未知的蛋白质，ARMC 10，并证明了ARMC 10的S45位点可以在体外和体内被AMPK磷酸化。此外，ARMC 10过表达足以促进线粒体分裂，而ARMC 10敲除阻止AMPK介导的线粒体分裂。这些结果表明，ARMC 10是AMPK的效应子，参与线粒体分裂和融合的动态调节。
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis. Although AMPK has been studied extensively in cellular processes, understanding of its substrates and downstream functional network, and their contributions to cell fate and disease development, remains incomplete. To elucidate the AMPK-dependent signaling pathways, we performed global quantitative phosphoproteomic analysis using wild-type and AMPK alpha 1/412-double knockout cells and discovered 160 AMPK-dependent phosphorylation sites. Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion.