Unraveling the molecular mechanisms underlying Ca2+-signaling modulation by CISD2, a wolfram syndrome-associated gene, and its interplay with Bcl-2 (CaCISD2)

The endoplasmic reticulum (ER) plays a key role in intracellular Ca2+ signaling. Dysregulation of these signals underly several diseases, including Wolfram syndrome, a condition associated with mutations in WFS1 en CISD2, resulting in neuronal defects and juvenile diabetes. Until now, no cure for Wolfram syndrome is available. Moreover, CISD2 has been identified as a longevity-associated gene.

Previous studies by others have linked CISD2 deficiency to deranged Ca2+ signalling, though the molecular basis remains unclear. Also, CISD2 can target the anti-apoptotic/anti-autophagic protein Bcl-2, promoting its cellular function. The Bcl-2 domain targeted by CISD2 is the BH4 domain. Fascinatingly, we previously showed Bcl-2’s BH4 domain binds to and inhibits IP3 and ryanodine receptors (IP3Rs and RyRs), intracellular Ca2+-release channels whose function is disturbed in Wolfram syndrome.

Here, we aim to investigate the mechanisms by which CISD2 modulates intracellular Ca2+ dynamics by controlling the Ca2+-flux properties of IP3Rs and RyRs and this property is affected by disease-linked mutations in CISD2. We will consider both direct modulation of these channels by CISD2 as well as indirect modulation through Bcl-2’s BH4 domain. These studies will be expanded towards cell models relevant for Wolfram syndrome. We envision that this work can contribute to a better understanding of the etiology of CISD2-linked Wolfram syndrome and may provide novel therapeutic strategies to tackle this disease.