Guo, Zhiqiang; Bergeron, Karl-Frédérik et Mounier, Catherine
(2025).
« Oleate Activates PLD2 Lipase and GEF Activity by Modulating Membrane
Microdomain Dynamics via S-acylation ». Prépublication.
(Montréal, Québec, Canada, Univerisité du Québec à Montréal, Sciences biologiques).
40 p.
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Résumé
Phospholipase D2 (PLD2) plays critical roles in cellular signaling, membrane dynamics, and cancer progression. Oleate (OA) has been shown to activate PLD2 and promote triple-negative breast cancer(TNBC) cell migration, but the underlying molecular mechanisms remain poorly understood. Using confocal microscopy, lipid raft isolation, and S-acylation assays, we show that OA enhanced PLD2 Sacylation at Cys223 and Cys224, disrupting its lipid raft localization, and consequently increasing its colocalization with PIP2-enriched microdomains. Furthermore, we identified PLD2 as a guanine nucleotide exchange factor (GEF) for Cdc42, with its GEF activity regulated by OA-dependent S-acylation and lipid raft dynamics. Mutation of the S-acylation sites or disruption of lipid rafts abolished PLD2-mediated Cdc42 activation and filopodia-like cell protrusion formation. These findings reveal a novel regulatory mechanism by which OA modulates PLD2 activity through S-acylation and membrane microdomain reorganization,providing new insights into the regulation of PLD2 in cell migration and signaling.
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