Dishevelled localization and function are differentially regulated by structurally distinct sterols.
| Autor: | Sengupta S; Cellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD, 57104, USA., Yaeger JDW; Cellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD, 57104, USA., Schultz MM; Cellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD, 57104, USA., Francis KR; Cellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD, 57104, USA.; Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, 57105, USA. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2024 May 15. Date of Electronic Publication: 2024 May 15. |
| DOI: | 10.1101/2024.05.14.593701 |
| Abstrakt: | The Dishevelled (DVL) family of proteins form supramolecular protein and lipid complexes at the cytoplasmic interface of the plasma membrane to regulate tissue patterning, proliferation, cell polarity, and oncogenic processes through DVL-dependent signaling, such as Wnt/β-catenin. While DVL binding to cholesterol is required for its membrane association, the specific structural requirements and cellular impacts of DVL-sterol association are unclear. We report that intracellular sterols which accumulate within normal and pathological conditions cause aberrant DVL activity. In silico and molecular analyses suggested orientation of the β- and α-sterol face within the DVL-PDZ domain regulates DVL-sterol binding. Intracellular accumulation of naturally occurring sterols impaired DVL2 plasma membrane association, inducing DVL2 nuclear localization via Foxk2. Changes to intracellular sterols also selectively impaired DVL2 protein-protein interactions This work identifies sterol specificity as a regulator of DVL signaling, suggests intracellular sterols cause distinct impacts on DVL activity, and supports a role for intracellular sterol homeostasis in cell signaling. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing or financial interests. |
| Databáze: | MEDLINE |
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