The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis.
The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis.
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DOI：
10.1016/j.molcel.2016.04.020
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发表时间：
2016-05-19
期刊：
影响因子：
16
通讯作者：
Kundu M
中科院分区：
文献类型：
--
作者：
Joo JH;Wang B;Frankel E;Ge L;Xu L;Iyengar R;Li-Harms X;Wright C;Shaw TI;Lindsten T;Green DR;Peng J;Hendershot LM;Kilic F;Sze JY;Audhya A;Kundu M
ULK1和ULK2被认为是启动自噬所必需的，并且Ulk1/2缺陷小鼠死于与自噬相关的缺陷。因此，我们使用条件性敲除方法来研究ULK1/2在大脑中的作用。虽然小鼠显示神经元变性，但神经元没有显示P62 +/泛素+内含物或异常膜结构的积累，这些在缺乏其他自噬基因的小鼠中观察到。相反，神经元死亡与未折叠蛋白反应（UPR）通路的激活相关。一个公正的蛋白质组学方法确定SEC16A作为ULK1/2相互作用的合作伙伴。ULK介导的SEC16A磷酸化调节内质网（ER）出口位点的组装和特定货物的ER到高尔基体的运输，这不需要其他自噬蛋白（例如ATG13）。ER到高尔基体运输的缺陷激活了ULK缺陷细胞中的UPR途径;这两个过程在SEC16A表达后被磷酸化模拟物取代逆转。因此，通过ULK1/2调节ER至高尔基体的运输对于细胞内稳态是必不可少的。
ULK1 and ULK2 are thought to be essential for initiating autophagy, and Ulk1/2-deficient mice die perinatally of autophagy-related defects. Therefore, we used a conditional-knockout approach to investigate the roles of ULK1/2 in the brain. Although the mice showed neuronal degeneration, the neurons showed no accumulation of P62+/ubiquitin+ inclusions or abnormal membranous structures, which are observed in mice lacking other autophagy genes. Rather, neuronal death was associated with activation of the unfolded protein response (UPR) pathway. An unbiased proteomics approach identified SEC16A as an ULK1/2-interacting partner. ULK-mediated phosphorylation of SEC16A regulated the assembly of endoplasmic reticulum (ER) exit sites and ER-to-Golgi trafficking of specific cargo, which did not require other autophagy proteins (e.g. ATG13). The defect in ER-to-Golgi trafficking activated the UPR pathway in ULK-deficient cells; both processes were reversed upon expression of SEC16A with a phosphomimetic substitution. Thus, the regulation of ER-to-Golgi trafficking by ULK1/2 is essential for cellular homeostasis.