Essential role of calcineurin in response to endoplasmic reticulum stress

Depletion of calcium ions (Ca(2+)) from the endoplasmic reticulum (ER) of yeast cells resulted in the activation of the unfolded protein response (UPR) signaling pathway involving Ire1p and Hac1p. The depleted ER also stimulated Ca(2+) influx at the plasma membrane through the Cch1p–Mid1p Ca(2+) channel and another system. Surprisingly, both Ca(2+) influx systems were stimulated upon accumulation of misfolded proteins in the ER even in the presence of Ca(2+). The ability of misfolded ER proteins to stimulate Ca(2+) influx at the plasma membrane did not require Ire1p or Hac1p, and Ca(2+) influx and signaling factors were not required for initial UPR signaling. However, activation of the Ca(2+) channel, calmodulin, calcineurin and other factors was necessary for long-term survival of cells undergoing ER stress. A similar calcium cell survival (CCS) pathway operates in the pathogenic fungi and promotes resistance to azole antifungal drugs. These findings reveal an unanticipated new regulatory mechanism that couples ER stress to Ca(2+) influx and signaling pathways, which help to prevent cell death and promote resistance to an important class of fungistatic drugs.