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bioRxiv · 10.1101/2023.08.19.553998

AP2A1 is upregulated upon replicative senescence of human fibroblasts to strengthen focal adhesions via integrin β1 translocation along stress fibers

Chantachotikul, P.·Liu, S.·Furukawa, K.·Deguchi, S.
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Abstract

Aging proceeds with accumulation of senescent cells in multiple organs. Senescent cells become large in size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on reorganization of actin stress fibers induced upon replicative senescence of human fibroblasts, typically used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of stress fibers, which are enlarged following the increase in the whole cell size. We then revealed that knockdown of AP2A1 in senescent cells suppresses key senescence-associated phenotypes, which include decreased cell area and lowered expression of major senescence markers. Meanwhile, AP2A1 overexpression in young cells induced the opposite effects that rather advance senescence, suggesting that AP2A1 may be used as a senescence marker. We found that AP2A1 is colocalized with integrin {beta}1, and both of them move linearly along stress fibers. We further observed that focal adhesions are enlarged in senescent cells to reinforce cell adhesions to the substrate. These results suggest that senescent cells maintain their large size by strengthening the anchorage to the substrate by supplying integrin {beta}1 via translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin {beta}1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.

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Chantachotikul, P., Liu, S., Furukawa, K., Deguchi, S.. 2023-08-20. AP2A1 is upregulated upon replicative senescence of human fibroblasts to strengthen focal adhesions via integrin β1 translocation along stress fibers. https://doi.org/10.1101/2023.08.19.553998

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