Abstract
Although senescent cells display various morphological changes including vacuole formation, it is still unclear how these processes are regulated. We have recently identified the gene, lymphocyte antigen 6 complex, locus D (LY6D), to be upregulated specifically in senescent cells. LY6D is a glycosylphosphatidylinositol-anchored cell-surface protein whose function remains unknown. Here, we analyzed the functional relationship between LY6D and the senescence processes. We found that overexpression of LY6D induced vacuole formation and knockdown of LY6D suppressed the senescence-associated vacuole formation. The LY6D-induced vacuoles were derived from macropinocytosis, a distinct form of endocytosis. Furthermore, Src family kinases and Ras were found to be recruited to membrane lipid rafts in an LY6D-dependent manner, and inhibition of their activity impaired the LY6D-induced macropinocytosis. Finally, reduction of senescent-cell survival induced by glutamine deprivation was recovered by albumin supplementation to the culture media in an LY6D-dependent manner. Because macropinocytosis acts as an amino acid supply route, these results suggest that LY6D-mediated macropinocytosis contributes to senescent-cell survival through the incorporation of extracellular nutrients.
Highlights
Lymphocyte antigen 6 complex, locus D (LY6D) is a membrane-bound protein attached to the cell surface via a
The vacuole formation associated with etoposide-induced senescence was observed in normal human diploid fibroblasts Hs68 cells (Fig. 1, E and F) in which the lymphocyte antigen 6 complex (LY6D) gene was previously reported to be upregulated during senescence [6]
The etoposide treatment induced the recruitment of Fyn, Lyn, and Ras to the raft, all of which were abolished by depletion of LY6D (Fig. 5E and Fig. S6C). These results suggest that a cluster of signaling proteins including Src family kinases (SFK) and Ras is formed in the lipid raft during senescence in an LY6D-dependent manner
Summary
Lymphocyte antigen 6 complex, locus D (LY6D) is a membrane-bound protein attached to the cell surface via a. We have found that LY6D is needed for the senescence-associated vacuole formation, which occurs through the induction of Ras-mediated macropinocytosis. LY6D-induced macropinocytosis can promote survival of senescent cells by the internalization of extracellular fluid under poor nutritional conditions.
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