Rcn1, the fission yeast homolog of human DSCR1, regulates arsenite tolerance independently from calcineurin.
Calcineurin (CN) is a conserved Ca 2+ /calmodulin-dependent phosphoprotein phosphatase that plays a key role in Ca 2+  signaling. Regulator of calcineurin 1 (RCAN1), also known as Down syndrome critical region gene 1 (DSCR1), interacts with calcineurin and inhibits calcineurin-dependent signaling in various organisms. Ppb1, the fission yeast calcineurin regulates Cl - -homeostasis, and Ppb1 deletion induces MgCl 2  hypersensitivity. Here, we characterize the conserved and novel roles of the fission yeast RCAN1 homolog rcn1 + . Consistent with its role as an endogenous calcineurin inhibitor, Rcn1 overproduction reproduced the calcineurin-null phenotypes, including MgCl 2  hypersensitivity and inhibition of calcineurin signaling upon extracellular Ca 2+  stimuli as evaluated by the nuclear translocation and transcriptional activation of the calcineurin substrate Prz1. Notably, overexpression of rcn1 +  causes hypersensitivity to arsenite, whereas calcineurin deletion induces arsenite tolerance, showing a phenotypic discrepancy between Rcn1 overexpression and calcineurin deletion. Importantly, although Rcn1 deletion induces modest sensitivities to arsenite and MgCl 2  in wild-type cells, the arsenite tolerance, but not MgCl 2  sensitivity, associated with Ppb1 deletion was markedly suppressed by Rcn1 deletion. Collectively, our findings reveal a previously unrecognized functional collaboration between Rcn1 and calcineurin, wherein Rcn1 not only negatively regulates calcineurin in the Cl -  homeostasis, but also Rcn1 mediates calcineurin signaling to modulate arsenite cytotoxicity.
Takasaki T, Bamba A, Kukita Y, Nishida A, Kanbayashi D, Hagihara K, Satoh R, Ishihara K, Sugiura R