Drought is a major abiotic stress that causes the yearly yield loss of maize,a crop cultured worldwide.Breeding drought-tolerant maize cultivars is a priority requirement of world agriculture.Clade A PP2C phosphatases (PP2C-A),which are conserved in most plant species,play important roles in abscisic acid (ABA) signaling and plant drought response.However,natural variations of PP2C-A genes that are directly associated with drought tolerance remain to be elucidated.Here,we conducted a candidate gene association analysis of the ZmPP2C-A gene family in a maize panel consisting of 368 varieties collected worldwide,and identified a drought responsive gene ZmPP2C-A10 that is tightly associated with drought tolerance.We found that the degree of drought tolerance of maize cultivars negatively correlates with the expression levels of ZmPP2C-A 10.ZmPP2C-A10,like its Arabidopsis orthologs,interacts with ZmPYL ABA receptors and ZmSnRK2 kinases,suggesting that ZmPP2C-A10 is involved in mediating ABA signaling in maize.Transgenic studies in maize and Arabidopsis confirmed that ZmPP2C-A10 functions as a negative regulator of drought tolerance.Further,a causal natural variation,deletion allele-338,which bears a deletion of ERSE (endoplasmic reticulum stress response element) in the 5’-UTR region of ZmPP2C-A10,was detected.This deletion causes the loss of endoplasmic reticulum (ER) stress-induced expression of ZmPP2C-A10,leading to increased plant drought tolerance.Our study provides direct evidence linking ER stress signaling with drought tolerance and genetic resources that can be used directly in breeding drought-tolerant maize cultivars.