Department of Molecular Genetics, The Ohio State University, Columbus Ohio 43210, USA.
Genetics. 2010 Jul;185(3):871-82. doi: 10.1534/genetics.110.116566. Epub 2010 May 3.
Autophagy is an evolutionarily conserved degradative pathway that has been implicated in a number of physiological events important for human health. This process was originally identified as a response to nutrient deprivation and is thought to serve in a recycling capacity during periods of nutritional stress. Autophagy activity appears to be highly regulated and multiple signaling pathways are known to target a complex of proteins that contains the Atg1 protein kinase. The data here extend these observations and identify a particular phosphorylation event on Atg1 as a potential control point within the autophagy pathway in Saccharomyces cerevisiae. This phosphorylation occurs at a threonine residue, T226, within the Atg1 activation loop that is conserved in all Atg1 orthologs. Replacing this threonine with a nonphosphorylatable residue resulted in a loss of Atg1 protein kinase activity and a failure to induce autophagy. This phosphorylation required the presence of a functional Atg1 kinase domain and two known regulators of Atg1 activity, Atg13 and Atg17. Interestingly, the levels of this modification were found to increase dramatically upon exposure to conditions that induce autophagy. In addition, T226 phosphorylation was associated with an autophosphorylated form of Atg1 that was found specifically in cells undergoing the autophagy process. In all, these data suggest that autophosphorylation within the Atg1 activation loop may represent a point of regulatory control for this degradative process.
自噬是一种进化上保守的降解途径，与许多对人类健康很重要的生理事件有关。这个过程最初被认为是对营养缺乏的反应，在营养压力时期被认为具有循环能力。自噬活性似乎受到高度调控，已知有多种信号通路靶向含有 Atg1 蛋白激酶的蛋白质复合物。这里的数据扩展了这些观察结果，并确定了酵母中 Atg1 上的一个特定磷酸化事件是自噬途径中的一个潜在控制点。该磷酸化发生在 Atg1 激活环中的苏氨酸残基 T226 上，该残基在所有 Atg1 同源物中都保守。用不可磷酸化的残基取代该苏氨酸导致 Atg1 蛋白激酶活性丧失，并导致自噬诱导失败。这种磷酸化需要有功能的 Atg1 激酶结构域和两个已知的 Atg1 活性调节剂 Atg13 和 Atg17。有趣的是，这种修饰的水平在诱导自噬的条件下会显著增加。此外，T226 磷酸化与 Atg1 的一种自身磷酸化形式有关，这种形式仅在经历自噬过程的细胞中发现。总之，这些数据表明，Atg1 激活环内的自身磷酸化可能是这个降解过程的一个调控控制点。
