Abstract
Many genes and signaling pathways have been found to be involved in cellular senescence program. In the present study, we have identified 16 senescence-associated genes by differential proteomic analysis of the normal human diploid fibroblast cell line, TIG-1, and focused on ATP6V0A2. The aim of this study is to clarify the role of ATP6V0A2, the causal gene for ARCL2, a syndrome of abnormal glycosylation and impaired Golgi trafficking, in cellular senescence program. Here we showed that ATP6V0A2 is critical for cellular senescence; impaired expression of ATP6V0A2 disperses the Golgi structure and triggers senescence, suggesting that ATP6V0A2 mediates these processes. FITC-lectin staining and glycoblotting revealed significantly different glycosylation structures in presenescent (young) and senescent (old) TIG-1 cells; reducing ATP6V0A2 expression in young TIG-1 cells yielded structures similar to those in old TIG-1 cells. Our results suggest that senescence-associated impaired expression of ATP6V0A2 triggers changes in Golgi structure and glycosylation in old TIG-1 cells, which demonstrates a role of ATP6V0A2 in cellular senescence program.
Highlights
SAG1 SAG2 SAG3 SAG4 SAG5 SAG6 SAG7 SAG8 SAG9 SAG10 SAG11 SAG12 SAG13 SAG14 SAG15 SAG16
We identified 16 novel senescence-associated genes (SAGs) by subtractive proteomic analysis in pre-senescent and senescent human normal diploid cells, TIG-1 (Fig. 1A and Table S1)
The expression patterns of some SAGs were not coincident with those obtained by proteomic analysis, the expression of ten SAGs were downregulated and those of 5 SAGs were upregulated in old TIG-1 cells
Summary
SAG1 SAG2 SAG3 SAG4 SAG5 SAG6 SAG7 SAG8 SAG9 SAG10 SAG11 SAG12 SAG13 SAG14 SAG15 SAG16. The exact mechanisms for the ATP6V0A2 defect-induced glycosylation abnormality are not fully understood. Glycosylation diseases are caused by defects in the machinery in the docking and fusion of transport vesicles, defects in protein sorting apparatus, and defects in Golgi pH homeostasis and membrane fusion. Considering at a cellular level, the structure of the Golgi complex is altered in senescent cells[12], which might lead to glycosylation abnormalities[8]. We assumed that ATP6V0A2 would play a key role in Golgi collapse and subsequent glycosylation abnormalities caused by cellular senescence. By investigating the role of ATP6V0A2 in the maintenance of the Golgi homeostasis and in the cellular senescence, we would clarify the target molecules and mechanisms for treating diseases caused by glycosylation abnormalities
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