Cs. Hemenway et al., VPH6 MUTANTS OF SACCHAROMYCES-CEREVISIAE REQUIRE CALCINEURIN FOR GROWTH AND ARE DEFECTIVE IN VACUOLAR H-ATPASE ASSEMBLY(), Genetics, 141(3), 1995, pp. 833-844
We have characterized a Saccharomyces cerevisiae mutant strain that is
hypersensitive to cyclosporin A (CsA) and FK506, immunosuppressants t
hat inhibit calcineurin, a serine-threonine-specific phosphatase (PP2B
). A single nuclear mutation, designated cev1 for calcineurin essentia
l for viability, is responsible for the CsA-FK506-sensitive phenotype.
The peptidyl-prolyl cis-trans isomerases cyclophilin A and FKBP12, re
spectively, mediate CsA and FK506 toxicity in the cev1 mutant strain.
We demonstrate that cev1 is an allele of the VPH6 gene and that vph6 m
utant strains fail to assemble the vacuolar H+-ATPase (V-ATPase). The
VPH6 gene was mapped on chromosome VIII and is predicted to encode a 1
81-amino acid (21 kD) protein with no identity to other known proteins
. Sire find that calcineurin is essential for viability in many mutant
strains with defects in V-ATPase function or vacuolar acidification.
In addition, we find that calcineurin modulates extracellular acidific
ation in response to glucose, which we propose occurs via calcineurin
regulation of the plasma membrane H+-ATPase PMA1. Taken together, our
findings suggest calcineurin plays a general role in the regulation of
cation transport and homeostasis.