AMPK对ULK1的磷酸化作用调节ULK1向线粒体的转运及线粒体自噬。

Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy.

作者信息

Tian Weili, Li Wen, Chen Yinqin, Yan Zeming, Huang Xia, Zhuang Haixia, Zhong Wangtao, Chen Yusen, Wu Wenxian, Lin Chunxia, Chen Hao, Hou Xiaoyan, Zhang Liangqing, Sui Senfang, Zhao Bin, Hu Zhe, Li Longxuan, Feng Du

机构信息

Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.

Department of Vascular Surgery, Thyroid and Mammary Gland Surgery, Guangdong Medical College, Zhanjiang 524001, China.

出版信息

FEBS Lett. 2015 Jul 8;589(15):1847-54. doi: 10.1016/j.febslet.2015.05.020. Epub 2015 May 14.

DOI:10.1016/j.febslet.2015.05.020

PMID:25980607

Abstract

UNC-51 like kinase (ULK1) translocates to dysfunctional mitochondria and is involved in mitophagy, but the mechanisms responsible for ULK1 activation and translocation remain unclear. Here, we found that hypoxia induces phosphorylation of ULK1 at Serine-555 by Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Unlike wild-type ULK1, an ULK1 (S555A) mutant cannot translocate to mitochondria in response to hypoxia. Inhibition or knockdown of AMPK prevents ULK1 translocation and inhibits mitophagy. Finally, the phospho-mimic ULK1 (S555D) mutant, but not ULK1 (S555A), rescues mitophagy in AMPK-knockdown cells. Thus, we conclude that AMPK-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress.

摘要

UNC-51样激酶（ULK1）转位至功能失调的线粒体并参与线粒体自噬，但负责ULK1激活和转位的机制仍不清楚。在此，我们发现缺氧诱导腺苷5'-单磷酸（AMP）激活的蛋白激酶（AMPK）使ULK1的丝氨酸555位点发生磷酸化。与野生型ULK1不同，ULK1（S555A）突变体在缺氧时不能转位至线粒体。抑制或敲低AMPK可阻止ULK1转位并抑制线粒体自噬。最后，模拟磷酸化的ULK1（S555D）突变体而非ULK1（S555A）可挽救AMPK敲低细胞中的线粒体自噬。因此，我们得出结论，AMPK依赖的ULK1磷酸化对于ULK1转位至线粒体以及对缺氧应激的线粒体自噬至关重要。