Atg13 Is Essential for Autophagy and Cardiac Development in Mice
Atg13 Is Essential for Autophagy and Cardiac Development in Mice
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DOI：
10.1128/mcb.01005-15
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发表时间：
2016-02-01
影响因子：
5.3
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
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作者：
Kaizuka, Takeshi;Mizushima, Noboru
自噬是一种主要的细胞内降解系统，通过自噬体将细胞质成分包裹并递送到溶酶体。自噬体的形成需要一组自噬相关（Atg）蛋白。在这些蛋白质中，由ULK 1（或ULK 2）、FIP 200、Atg 13和Atg 101组成的ULK 1复合物在初始步骤起作用。先前的研究表明，ULK 1和FIP 200也在自噬以外的途径中发挥作用。然而，Atg 13和Atg 101是否与ULK 1和FIP 200类似仍然未知。在本研究中，我们产生了Atg 13基因敲除小鼠。与FIP 200缺陷小鼠一样，Atg 13缺陷小鼠在子宫内死亡，这与大多数其他类型的Atg缺陷小鼠不同。atg 13缺陷的胚胎表现出生长迟缓和心肌生长缺陷。在培养的成纤维细胞中，Atg 13缺陷在上游步骤阻断自噬体形成。此外，对肿瘤坏死因子α（TNF-α）诱导的细胞凋亡的敏感性通过Atg 13或FIP 200的缺失而增强，但不通过其他Atg蛋白，以及通过同时缺失ULK 1和ULK 2。这些结果表明，Atg 13具有自噬和非自噬功能，后者对心脏发育至关重要，可能与FIP 200共享，但不与ULK 1/2共享。
Autophagy is a major intracellular degradation system by which cytoplasmic components are enclosed by autophagosomes and delivered to lysosomes. Formation of the autophagosome requires a set of autophagy-related (Atg) proteins. Among these proteins, the ULK1 complex, which is composed of ULK1 (or ULK2), FIP200, Atg13, and Atg101, acts at an initial step. Previous studies showed that ULK1 and FIP200 also function in pathways other than autophagy. However, whether Atg13 and Atg101 act similarly to ULK1 and FIP200 remains unknown. In the present study, we generated Atg13 knockout mice. Like FIP200-deficient mice, Atg13-deficient mice die in utero, which is distinct from most other types of Atg-deficient mice. Atg13-deficient embryos show growth retardation and myocardial growth defects. In cultured fibroblasts, Atg13 deficiency blocks autophagosome formation at an upstream step. In addition, sensitivity to tumor necrosis factor alpha (TNF-alpha)-induced apoptosis is enhanced by deletion of Atg13 or FIP200, but not by other Atg proteins, as well as by simultaneous deletion of ULK1 and ULK2. These results suggest that Atg13 has both autophagic and nonautophagic functions and that the latter are essential for cardiac development and likely shared with FIP200 but not with ULK1/2.