Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
SYSBIO, Centre of Systems Biology, Milan, Italy.
Sci Rep. 2016 Jun 16;6:27942. doi: 10.1038/srep27942.
Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage.
钙稳态对真核细胞的生存至关重要。钙离子作为几种信号转导途径中的酶辅助因子和第二信使,控制着许多重要的生物过程。在内质网(ER)中,钙离子浓度受到严格调节,以确保分泌蛋白的正确折叠和加工。通过使用模式生物酿酒酵母,我们发现钙缺乏会导致细胞生长和代谢减慢。未折叠蛋白在内质网钙耗尽腔室中的积累(内质网应激)会触发未折叠蛋白反应(UPR),并产生氧化应激状态,降低细胞活力。在快速可发酵碳源上生长时,这些影响更为严重,可通过降低蛋白质合成率或诱导细胞呼吸来减轻。钙稳态、蛋白质生物合成和未折叠蛋白反应紧密交织在一起,面临钙饥饿的后果取决于细胞能量产生是否与合成代谢功能的需求相平衡。我们的发现证实,连接内质网钙平衡失调与内质网应激和 UPR 信号的联系在进化上是保守的,并强调了代谢在调节钙缺乏引起的影响方面的关键作用。