A small molecule suppressor of FK506 that targets the mitochondria and modulates ionic balance in Saccharomyces cerevisiae.
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.
Butcher
Rebecca A
RA
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Schreiber
Stuart L
SL
D017209:Apoptosis / Q000502:physiology*; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003510:Cyclohexanes / Q000302:isolation & purification* / Q000494:pharmacology; D004268:DNA-Binding Proteins; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018272:Porins / Q000737:chemistry / Q000378:metabolism; D011494:Protein Kinases; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction / Q000235:genetics; D012965:Sodium Chloride; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000037:antagonists & inhibitors*
D003510:Cyclohexanes; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D018272:Porins; C482297:SKF1 compound; D029701:Saccharomyces cerevisiae Proteins; D012965:Sodium Chloride; D011494:Protein Kinases; C102035:YPD1 protein, S cerevisiae; D019703:Calcineurin; D016559:Tacrolimus