The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy
The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy
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DOI：
10.4161/auto.7.7.15450
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发表时间：
2011-07-01
期刊：
影响因子：
13.3
通讯作者：
Tournier, Cathy
中科院分区：
文献类型：
--
作者：
Lee, Eun-Ju;Tournier, Cathy
自噬是一种进化上保守的细胞自我消化以适应包括饥饿在内的各种应激的生理过程。其分子基础涉及自噬相关（Atg）基因家族编码的蛋白质的协同激活。最好的特点是丝氨酸/苏氨酸蛋白激酶Atg 1在酵母中，这似乎是必不可少的早期阶段的自噬。在哺乳动物中，五个Atg 1同源物已被确定为不协调的（N51）样激酶1至4和STK 36。ULK 1和ULK 2是该家族中最密切相关的成员，在其蛋白激酶结构域中共享78%的同源性。然而，ULK 1和ULK 2在哺乳动物自噬中的具体功能尚未完全了解。在这里，我们证明了ULK 1和ULK 2是功能冗余的蛋白激酶，需要在营养缺乏的条件下在成纤维细胞中介导自噬。相比之下，ULK 1，而不是ULK 2，是关键的诱导小脑颗粒神经元（CGN）的自噬反应，低钾浓度在无血清条件下。此外，我们发现ULK 1在神经元中具有细胞保护功能。总之，这些结果提供了强有力的遗传证据，表明ULK 1是自噬信号通路的重要组成部分。ULK 2补偿ULK 1功能丧失的能力是细胞类型特异性的。
Autophagy is an evolutionarily conserved physiological process of self-digestion by a cell to adapt to various stresses, including starvation. Its molecular basis involves the concerted activation of proteins encoded by the family of autophagy-related (Atg) genes. The best characterized is the serine/threonine protein kinase Atg1 in yeast which appears to be essential at the early stage of autophagy. In mammals, five Atg1 homologues have been identified as uncoordinated (UNC) 51-like kinase 1 to 4 and STK36. ULK1 and ULK2 are the most closely related members of the family, sharing 78% homology within their protein kinase domains. However, the specific function of ULK1 and ULK2 in mammalian autophagy is not fully understood. Here, we demonstrate that ULK1 and ULK2 are functionally redundant protein kinases required to mediate autophagy under nutrient-deprived conditions in fibroblasts. In contrast, ULK1, but not ULK2, is critical to induce the autophagic response of cerebellar granule neurons (CGN) to low potassium concentration in serum-free conditions. Furthermore, we found that ULK1 has a cytoprotective function in neurons. Together, these results provide strong genetic evidence that ULK1 is an essential component of the autophagic signaling pathway. The ability of ULK2 to compensate for the loss of ULK1 function is cell-type specific.