Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2
Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2
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DOI：
10.4161/auto.23066
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发表时间：
2013-03-01
期刊：
影响因子：
13.3
通讯作者：
Chan, Edmond Y. W.
中科院分区：
文献类型：
--
作者：
McAlpine, Fiona;Williamson, Leon E.;Chan, Edmond Y. W.
巨自噬，通常称为自噬，是一种蛋白质降解途径，在细胞中组成性发生，但也可以由应激源如营养饥饿或蛋白质聚集诱导。自噬与多种疾病机制有关，包括神经变性和癌症，具有肿瘤抑制和致癌作用。不协调51样激酶1（ULK 1）是一种重要的自噬蛋白，靠近分级调节途径的顶点，接收来自主营养传感器MTOR和AMP激活蛋白激酶（AMPK）的信号。在哺乳动物中，ULK 1有一个密切的同源物，ULK 2，尽管它们的功能差异还不清楚。在这里，我们发现ULK 1和ULK 2都可以支持营养饥饿后的自噬激活。在小鼠胚胎成纤维细胞中，氨基酸或葡萄糖饥饿后增加的自噬仅在ULK 1和ULK 2的联合丢失时被破坏。PtdIns 3 P的产生和WIPI 2或ZFYVE 1/DFCP 1在氨基酸饥饿后向吞噬细胞的募集被组合的Ulk 1/2双敲除阻断。葡萄糖饥饿后的自噬激活不涉及WIPI 1或WIPI 2的募集以形成自噬体。与PtdIns 3 P非依赖性机制一致，葡萄糖依赖性自噬对渥曼青霉素具有抗性。我们的研究结果支持ULK 1和ULK 2之间的功能冗余，用于营养依赖性自噬激活，并进一步强调了响应氨基酸和葡萄糖剥夺的差异途径。
Macroautophagy, commonly referred to as autophagy, is a protein degradation pathway that occurs constitutively in cells, but can also be induced by stressors such as nutrient starvation or protein aggregation. Autophagy has been implicated in multiple disease mechanisms including neurodegeneration and cancer, with both tumor suppressive and oncogenic roles. Uncoordinated 51-like kinase 1 (ULK1) is a critical autophagy protein near the apex of the hierarchal regulatory pathway that receives signals from the master nutrient sensors MTOR and AMP-activated protein kinase (AMPK). In mammals, ULK1 has a close homolog, ULK2, although their functional distinctions have been unclear. Here, we show that ULK1 and ULK2 both function to support autophagy activation following nutrient starvation. Increased autophagy following amino acid or glucose starvation was disrupted only upon combined loss of ULK1 and ULK2 in mouse embryonic fibroblasts. Generation of PtdIns3P and recruitment of WIPI2 or ZFYVE1/DFCP1 to the phagophore following amino acid starvation was blocked by combined Ulk1/2 double knockout. Autophagy activation following glucose starvation did not involve recruitment of either WIPI1 or WIPI2 to forming autophagosomes. Consistent with a PtdIns3P-independent mechanism, glucose-dependent autophagy was resistant to wortmannin. Our findings support functional redundancy between ULK1 and ULK2 for nutrient-dependent activation of autophagy and furthermore highlight the differential pathways that respond to amino acid and glucose deprivation.