Phospholipid scramblase 1 (PLSCR1) is a novel substrate of NEDD4-2 (NEDD4L) mediated ubiquitination

Shabbar, M; Manning, JA; Lim, Y; Shah, SS; Sinha, D; Nikolic, A; Sandow, JJ; Kumar, S

Author(s): Shabbar, M; Manning, JA; Lim, Y; Shah, SS; Sinha, D; Nikolic, A; Sandow, JJ; Kumar, S;
Details: Publication Year 2025-08-20,Volume 11,Issue #1,Page 393
Journal Title: Cell Death Discovery
Abstract: NEDD4-2 (human NEDD4L), a ubiquitin ligase, plays an essential role in regulating a number of membrane proteins, including ion channels and transporters. In the kidney, NEDD4-2 deletion results in a progressive loss of tubular cells and salt-sensitive chronic kidney disease. While deregulation of sodium homeostasis due to increased levels and function of the epithelial sodium channel (ENaC) and sodium chloride transporter (NCC), both NEDD4-2 substrates, plays a critical role in kidney damage in this model, other ubiquitination targets may also be important. Here, we employed an affinity purification mass spectrometry approach to identify additional interactors of NEDD4-2 in kidney cells and discovered phospholipid scramblase 1 (PLSCR1) as a new NEDD4-2 substrate. We show that PLSCR1 is a direct interactor and substrate of NEDD4-2. As a result, NEDD4-2 deficiency both in cultured cells and in mouse kidney resulted in increased levels of PLSCR1 protein. We observed increased phosphatidyl serine exposure in NEDD4-2 knockout cells in response to both calcium and apoptotic stimuli and this phenotype was reversed when NEDD4-2 expression was restored. Consistently, apoptotic cells lacking NEDD4-2 showed a higher rate of macrophage clearance. Together, these results indicate that PLSCR1 is a novel substrate of NEDD4-2-mediated ubiquitination and that NEDD4-2 regulates PLSCR1 protein stability and function.
Publisher: Springer Nature
Research Division(s): Structural Biology
PubMed ID: 40835608/
Publisher's Version: https://doi.org/10.1038/s41420-025-02700-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41420-025-02700-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-05 09:30:40

Last Modified: 2025-12-05 09:30:58