Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy
Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy
复制标题
蛋白质磷酸化-乙酰化级联将生长因子剥夺与自噬联系起来
DOI：
10.4161/auto.20959
复制
发表时间：
2012-09-01
期刊：
影响因子：
13.3
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Lin, Shu-Yong;Li, Terytty Yang;Lin, Sheng-Cai
与单细胞生物不同，后生动物细胞需要细胞外生长因子的存在来利用环境营养。然而，其潜在机制尚不清楚。我们已经描绘了一个途径，其中糖原合成酶激酶3（GSK 3）在缺乏生长因子的细胞中磷酸化并激活乙酰转移酶KAT 5/TIP 60，这反过来又刺激蛋白激酶ULK 1引发自噬。用不能被GSK 3磷酸化的Kat 5（S86 A）替换Kat 5/Tip 60基因的细胞对血清饥饿诱导的自噬具有抗性。ULK 1上的乙酰化位点被定位到K162和K606，乙酰化缺陷突变体ULK 1（K162，606 R）显示出激酶活性降低，并且无法挽救Ulk 1（-/-）小鼠胚胎成纤维细胞中的自噬，这表明乙酰化对ULK 1的激活至关重要。GSK 3-KAT 5-ULK 1级联似乎对细胞特异性地感知生长因子，因为KAT 5磷酸化在葡萄糖剥夺下不增强。与所有真核生物中保守的葡萄糖饥饿-自噬途径不同，生长因子剥夺反应途径可能是后生动物所特有的。
Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5(S86A) that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1(K162,606R) displays reduced kinase activity and fails to rescue autophagy in Ulk1(-/-) mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms.