SUMMARY
Loss of membrane raft integrity, metabolic dysregulation and inflammation are hallmarks of chronic diseases and aging. It is not well understood how the stress response itself may contribute to the manifestation of these common traits. To explore this question, we screened the model organism S. cerevisiae, for the secretion of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a proxy for membrane raft instability. It is shown here that the multiple cellular dysfunctions previously described for a defect in the methylation pathway for phosphatidyl choline (PC) synthesis (opi3Δ) are linked with GPI-APs secretion. They collectively result from the sustained activation of the mitogen-activated protein kinase (MAPK) Hog1p. Through modifying the dihydroxyacetone phosphate / glycerol-3-phosphate ratio, activated MAPK promotes phospholipid gene de-repression and interferes with GPI anchor synthesis. Rewiring the three carbon metabolism, namely by deleting the mitochondrial glycerol phosphate dehydrogenase, abrogated the opi3Δ mutant pleiotropic phenotypes identifying key targets to counteract MAPK-induced cellular dysfunctions.
Competing Interest Statement
The authors have declared no competing interest.