Butcher Rebecca A, Schreiber Stuart L
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Chem Biol. 2003 Jun;10(6):521-31. doi: 10.1016/s1074-5521(03)00108-x.
FK506 inhibits the evolutionarily conserved, Ca(2+)-dependent phosphatase calcineurin, which in yeast is essential for growth during sodium stress. We undertook a chemical genetic modifier screen to identify small molecules that suppress the ability of FK506 to inhibit yeast growth in high NaCl. One of these small molecule suppressors, SFK1 (suppressor of FK506 1), causes a mitochondrially induced death in low salt, concomitant with the release of reactive oxygen species. Biochemically, SFK1 interacts with Por1p, a channel protein in the outer mitochondrial membrane, suggesting that SFK1 interacts with the mitochondria directly. A genome-wide screen of yeast deletion strains for hypersensitivity to SFK1 yielded several strains with impaired mitochondrial function, as well as several with reduced sodium tolerance. Our data link ionic balance to mitochondrial function and suggest a role for calcineurin in mediating this signaling network.
FK506抑制进化上保守的、Ca(2+)依赖性磷酸酶钙调神经磷酸酶，该酶在酵母中对于钠胁迫期间的生长至关重要。我们进行了一项化学遗传修饰剂筛选，以鉴定抑制FK506在高NaCl中抑制酵母生长能力的小分子。这些小分子抑制剂之一，SFK1（FK506抑制剂1），在低盐条件下导致线粒体诱导的死亡，并伴有活性氧的释放。从生化角度来看，SFK1与线粒体外膜中的通道蛋白Por1p相互作用，这表明SFK1直接与线粒体相互作用。对酵母缺失菌株进行全基因组筛选以检测对SFK1的超敏感性，结果产生了几个线粒体功能受损的菌株，以及几个钠耐受性降低的菌株。我们的数据将离子平衡与线粒体功能联系起来，并表明钙调神经磷酸酶在介导该信号网络中发挥作用。
