Reciprocal rescue of Wolfram syndrome by two causative genes.

Wolfram syndrome (WS) is marked by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. The causative genes, WFS1 and CISD2, correspond to WS types 1 and 2, respectively. Here, we establish their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP₃R) activity, demonstrating their ability to restore reduced IP₃R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, our Drosophila WS models lacking dWFS1 or dCISD exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of dWFS1 and dCISD in the flies alleviates their phenotypes. We have engineered a peptide containing the CDGSH domain of CISD2, critical for its interaction with IP₃R. Overexpression of our CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes.