Possik Elite, Ajisebutu Andrew, Manteghi Sanaz, Gingras Marie-Claude, Vijayaraghavan Tarika, Flamand Mathieu, Coull Barry, Schmeisser Kathrin, Duchaine Thomas, van Steensel Maurice, Hall David H, Pause Arnim
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
PLoS Genet. 2015 Oct 6;11(10):e1005520. doi: 10.1371/journal.pgen.1005520. eCollection 2015 Oct.
Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5'-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis.
适应渗透压环境变化的机制是细胞和机体生存的基础。在这里，我们在秀丽隐杆线虫（C. elegans）中鉴定出一条新的抗渗透应激途径，该途径依赖于代谢主调节器5'-AMP激活蛋白激酶（AMPK）及其负调节因子卵泡抑素（FLCN）。FLCN-1是肿瘤抑制因子FLCN的线虫直系同源物，与Birt-Hogg-Dubé（BHD）肿瘤综合征相关。我们发现，flcn-1突变体通过组成型AMPK依赖性糖原储备积累，表现出对高渗应激的抗性增加。在暴露于高渗应激时，糖原储备迅速降解，通过甘油-3-磷酸脱氢酶（gpdh-1和gpdh-2）的转录上调，导致有机渗透剂甘油大量积累。重要的是，flcn-1突变体和野生型动物的高渗应激抗性在AMPK、糖原合酶、糖原磷酸化酶缺失或gpdh-1和gpdh-2酶同时缺失时受到强烈抑制。我们的研究首次表明，动物通常表现出AMPK依赖性糖原储备，可用于快速适应能量应激或高渗应激。重要的是，我们发现糖原在缺乏FLCN的小鼠肾脏和一名BHD患者的肾肿瘤中积累。我们的研究结果表明糖原具有双重作用，作为能量供应和渗透剂产生的储备，这两个过程可能都支持肿瘤发生。
