Singh Jaspal, Tyers Mike
Department of Molecular Genetics, University of Toronto, Ontario, Canada.
Genes Dev. 2009 Aug 15;23(16):1944-58. doi: 10.1101/gad.1804409.
The coupling of environmental conditions to cell growth and division is integral to cell fitness. In Saccharomyces cerevisiae, the transcription factor Sfp1 couples nutrient status to cell growth rate by controlling the expression of ribosome biogenesis (Ribi) and ribosomal protein (RP) genes. Sfp1 is localized to the nucleus in rich nutrients, but upon nutrient limitation or target of rapamycin (TOR) pathway inhibition by rapamycin, Sfp1 rapidly exits the nucleus, leading to repression of the Ribi/RP regulons. Through systematic cell-based screens we found that many components of the secretory system influence Sfp1 localization. Notably, the essential Rab escort protein Mrs6 exhibited a nutrient-sensitive interaction with Sfp1. Overexpression of Mrs6 prevented nuclear localization of Sfp1 in rich nutrients, whereas loss of Mrs6 resulted in nuclear Sfp1 localization in poor nutrients. These effects were specific to Sfp1 and independent of the protein kinase C (PKC) pathway, suggesting that Mrs6 lies in a distinct branch of TOR and ribosome biogenesis regulation. Rapamycin-resistant alleles of MRS6 were defective in the cytoplasmic retention of Sfp1, the control of cell size, and in the repression of the Ribi/RP regulons. The Sfp1-Mrs6 interaction is a nexus for growth regulation that links the secretory system and TOR-dependent nutrient signaling to ribosome biogenesis.
环境条件与细胞生长和分裂的耦合对于细胞适应性至关重要。在酿酒酵母中，转录因子Sfp1通过控制核糖体生物合成（Ribi）和核糖体蛋白（RP）基因的表达，将营养状态与细胞生长速率联系起来。在营养丰富时，Sfp1定位于细胞核，但在营养限制或雷帕霉素抑制雷帕霉素靶蛋白（TOR）途径时，Sfp1迅速离开细胞核，导致Ribi/RP调控子的抑制。通过基于细胞的系统筛选，我们发现分泌系统的许多成分影响Sfp1的定位。值得注意的是，必需的Rab护送蛋白Mrs6与Sfp1表现出营养敏感的相互作用。Mrs6的过表达阻止了Sfp1在营养丰富时的核定位，而Mrs6的缺失导致Sfp1在营养贫乏时定位于细胞核。这些效应是Sfp1特有的，且独立于蛋白激酶C（PKC）途径，表明Mrs6位于TOR和核糖体生物合成调控的一个不同分支中。MRS6的雷帕霉素抗性等位基因在Sfp1的细胞质保留、细胞大小控制以及Ribi/RP调控子的抑制方面存在缺陷。Sfp1-Mrs6相互作用是生长调控的一个枢纽，它将分泌系统和TOR依赖性营养信号与核糖体生物合成联系起来。
