Ham Su Jin, Yoon Eunju, Lee Da Hyun, Kim Sehyeon, Yoo Heesuk, Chung Jongkyeong
Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea.
School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
EMBO Rep. 2025 May;26(9):2459-2482. doi: 10.1038/s44319-025-00436-2. Epub 2025 Apr 3.
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 (IPR) activity, demonstrating their ability to restore reduced IPR 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 IPR. 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.
沃夫勒姆综合征（WS）的特征为青少年起病的糖尿病、视神经萎缩、尿崩症和感音神经性听力损失。致病基因WFS1和CISD2分别对应于1型和2型WS。在此，我们证实了它们对于肌醇1,4,5 - 三磷酸受体（IPR）活性的相互不可或缺性，证明了它们能够恢复WFS1或CISD2缺陷的哺乳动物细胞中降低的IPR活性。此外，我们缺乏dWFS1或dCISD的果蝇WS模型表现出与WS患者类似的糖尿病样表型，并且果蝇中dWFS1和dCISD的过表达减轻了它们的表型。我们设计了一种包含CISD2的CDGSH结构域的肽，该结构域对于其与IPR的相互作用至关重要。我们的CISD2肽的过表达或用其细胞穿透肽（CPP）偶联形式处理可恢复WFS1或CISD2缺陷细胞中的钙稳态，并且过表达同源的dCISD肽可抑制WS模型果蝇中的糖尿病样表型。这些发现强调了WFS1和CISD2在ER钙调节中的复杂参与，并为WS相关糖尿病提供了潜在的治疗前景。
