Rashida Zeenat, Srinivasan Rajalakshmi, Cyanam Meghana, Laxman Sunil
Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore 560065, India.
Manipal Academy of Higher Education, Manipal 576104, India.
Sci Adv. 2021 Apr 14;7(16). doi: 10.1126/sciadv.abe5544. Print 2021 Apr.
In changing environments, cells modulate resource budgeting through distinct metabolic routes to control growth. Accordingly, the TORC1 and SNF1/AMPK pathways operate contrastingly in nutrient replete or limited environments to maintain homeostasis. The functions of TORC1 under glucose and amino acid limitation are relatively unknown. We identified a modified form of the yeast TORC1 component Kog1/Raptor, which exhibits delayed growth exclusively during glucose and amino acid limitations. Using this, we found a necessary function for Kog1 in these conditions where TORC1 kinase activity is undetectable. Metabolic flux and transcriptome analysis revealed that Kog1 controls SNF1-dependent carbon flux apportioning between glutamate/amino acid biosynthesis and gluconeogenesis. Kog1 regulates SNF1/AMPK activity and outputs and mediates a rapamycin-independent activation of the SNF1 targets Mig1 and Cat8. This enables effective glucose derepression, gluconeogenesis activation, and carbon allocation through different pathways. Therefore, Kog1 centrally regulates metabolic homeostasis and carbon utilization during nutrient limitation by managing SNF1 activity.
在不断变化的环境中，细胞通过不同的代谢途径调节资源分配以控制生长。因此，TORC1和SNF1/AMPK途径在营养丰富或有限的环境中发挥相反作用以维持体内平衡。TORC1在葡萄糖和氨基酸限制条件下的功能相对未知。我们鉴定出酵母TORC1组分Kog1/Raptor的一种修饰形式，其仅在葡萄糖和氨基酸限制期间表现出生长延迟。利用这一发现，我们发现在TORC1激酶活性无法检测到的这些条件下，Kog1具有必要功能。代谢通量和转录组分析表明，Kog1控制SNF1依赖的碳通量在谷氨酸/氨基酸生物合成和糖异生之间的分配。Kog1调节SNF1/AMPK活性及其输出，并介导SNF1靶标Mig1和Cat8的雷帕霉素非依赖性激活。这使得能够通过不同途径有效地解除葡萄糖阻遏、激活糖异生和进行碳分配。因此，Kog1通过管理SNF1活性在营养限制期间集中调节代谢稳态和碳利用。
