An Autophagy-Independent Role for ATG41 in Sulfur Metabolism During Zinc Deficiency
An Autophagy-Independent Role for ATG41 in Sulfur Metabolism During Zinc Deficiency
复制标题
DOI：
10.1534/genetics.117.300679
复制
发表时间：
2018-03-01
期刊：
影响因子：
3.3
通讯作者：
Eide, David J.
中科院分区：
文献类型：
--
作者：
Bucci, Michael D.;Weisenhorn, Erin;Eide, David J.
酿酒酵母的 Zap1 转录因子是基因组对锌缺乏反应的关键调节因子。锌缺乏期间受 Zap1 调节的基因之一是自噬相关基因 ATG41。在这里，我们报告说 Atg41 是缺锌条件下生长所必需的，但当锌丰富或其他金属受到限制时则不需要。与 Atg41 在巨自噬中的作用一致，我们发现营养性锌缺乏会诱导自噬，而 ATG41 的突变会减弱这种反应。多项实验表明，ATG41 功能对缺锌期间生长的重要性并不是因为它在巨自噬中的作用，而是因为一种或多种独立于自噬的功能。例如，雷帕霉素处理完全诱导缺锌 atg41 Delta 突变体的自噬，但未能改善生长。此外，atg41 Delta 突变体表现出比其他几种测试的自噬突变体严重得多的生长缺陷，并且 atg41 Delta 突变体表现出热休克因子 1 活性增加，这是蛋白质稳态应激的指标，而其他自噬突变体则没有。通过分析 atg41 Delta 突变体在从锌充足条件过渡到锌缺乏条件期间的转录组，表明 ATG41 在锌缺乏期间在硫代谢中具有独立于自噬的功能。硫代谢物分析证实，缺锌细胞中蛋氨酸、同型半胱氨酸和半胱氨酸的正常积累需要 Atg41。因此，我们得出结论，Atg41 在锌缺乏期间在巨自噬和硫代谢中发挥作用。
The Zap1 transcription factor of Saccharomyces cerevisiae is a key regulator in the genomic responses to zinc deficiency. Among the genes regulated by Zap1 during zinc deficiency is the autophagy-related gene ATG41. Here, we report that Atg41 is required for growth in zinc-deficient conditions, but not when zinc is abundant or when other metals are limiting. Consistent with a role for Atg41 in macroautophagy, we show that nutritional zinc deficiency induces autophagy and that mutation of ATG41 diminishes that response. Several experiments indicated that the importance of ATG41 function to growth during zinc deficiency is not because of its role in macroautophagy, but rather is due to one or more autophagy-independent functions. For example, rapamycin treatment fully induced autophagy in zinc-deficient atg41 Delta mutants but failed to improve growth. In addition, atg41 Delta mutants showed a far more severe growth defect than any of several other autophagy mutants tested, and atg41 Delta mutants showed increased Heat Shock Factor 1 activity, an indicator of protein homeostasis stress, while other autophagy mutants did not. An autophagy-independent function for ATG41 in sulfur metabolism during zinc deficiency was suggested by analyzing the transcriptome of atg41 Delta mutants during the transition from zinc-replete to -deficient conditions. Analysis of sulfur metabolites confirmed that Atg41 is needed for the normal accumulation of methionine, homocysteine, and cysteine in zinc-deficient cells. Therefore, we conclude that Atg41 plays roles in both macroautophagy and sulfur metabolism during zinc deficiency.