Molecular biology reports · 2026
Effect of Glycosylphosphatidylinositol-specific phospholipase D1 knockout on the expression of antioxidant enzymes and sirtuin.
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Lee Si Eon, Kim Moon-Moo
Аннотация
BACKGROUND: Glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1) is a membrane-associated enzyme that modulates diverse cellular processes through the cleavage of glycosylphosphatidylinositol (GPI)-anchored proteins. Although recent studies have linked circulating Gpld1 to exercise-induced rejuvenation, its cell-autonomous role in coordinating redox homeostasis, melanogenesis, and cellular aging has not been fully elucidated.
METHODS AND RESULTS: To address this, a stable Gpld1 knockout (KO) was generated in B16F1 melanoma cells using CRISPR/Cas9-mediated genome editing to investigate whether loss of Gpld1 induces aging-associated phenotypes and redox imbalance. Gpld1 KO cells exhibited senescence-like features, as evidenced by increased senescence-associated β-galactosidase (SA-β-gal) activity, accompanied by disrupted redox homeostasis and markedly enhanced melanin synthesis. In the context of skin aging, hyperpigmentation often accompanies senescence-associated changes and thus represents a relevant phenotypic readout in this model. Gene and protein expression analyses revealed coordinated remodeling of multiple aging-associated signaling pathways. Specifically, SIRT1 and the redox repair enzyme MsrA were downregulated, whereas SIRT7, forkhead box O1 (FoxO1), phosphorylated FoxO1 (p-FoxO1), and Caspase-1 were markedly upregulated. Reduced steady-state reactive oxygen species (ROS) levels detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) likely reflect compensatory activation of antioxidant signaling pathways rather than the absence of oxidative stress.
CONCLUSION: Collectively, these findings demonstrate that Gpld1 KO induces Senescence-like features, alters redox homeostasis, and, in melanocytic cells, manifests as enhanced melanogenesis. These results identify Gpld1 as a previously unrecognized regulator of oxidative stress-driven aging and pigmentation, suggesting its potential relevance to aging-related hyperpigmentation and redox imbalance.
METHODS AND RESULTS: To address this, a stable Gpld1 knockout (KO) was generated in B16F1 melanoma cells using CRISPR/Cas9-mediated genome editing to investigate whether loss of Gpld1 induces aging-associated phenotypes and redox imbalance. Gpld1 KO cells exhibited senescence-like features, as evidenced by increased senescence-associated β-galactosidase (SA-β-gal) activity, accompanied by disrupted redox homeostasis and markedly enhanced melanin synthesis. In the context of skin aging, hyperpigmentation often accompanies senescence-associated changes and thus represents a relevant phenotypic readout in this model. Gene and protein expression analyses revealed coordinated remodeling of multiple aging-associated signaling pathways. Specifically, SIRT1 and the redox repair enzyme MsrA were downregulated, whereas SIRT7, forkhead box O1 (FoxO1), phosphorylated FoxO1 (p-FoxO1), and Caspase-1 were markedly upregulated. Reduced steady-state reactive oxygen species (ROS) levels detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) likely reflect compensatory activation of antioxidant signaling pathways rather than the absence of oxidative stress.
CONCLUSION: Collectively, these findings demonstrate that Gpld1 KO induces Senescence-like features, alters redox homeostasis, and, in melanocytic cells, manifests as enhanced melanogenesis. These results identify Gpld1 as a previously unrecognized regulator of oxidative stress-driven aging and pigmentation, suggesting its potential relevance to aging-related hyperpigmentation and redox imbalance.