VAP mediated ER contact with lysosome regulates cellular senescence in epithelial cells

Abstract

Cellular senescence is characterized by irreversible cell cycle arrest and has been implicated to have a strong relation with many age-related diseases. Not only is senescence a response to cell damage, but the inflammatory markers secreted by senescent cells contribute further to aging. After an initial exposure to stress and damage, a feed-forward cycle of senescent cells causes an increase in chronic inflammation and senescence-associated secretory phenotypes. The different causes and markers of senescent phenotypes have provided insight of the concept, but still the understanding remains shallow due to the degree of heterogeneity in senescent state.

Here, we found the possibility that the contact of endoplasmic reticulum (ER) with other organelles could have a significant role in regulating cellular senescence. VAP proteins, which are ubiquitous ER- resident tail-anchored membrane proteins, are well-known as the major proteins controlling the contact between ER and other organelles through the membrane. By hindering the expression of VAPA and VAPB, we were able to observe an increase in cellular senescence in epithelial cells. We also noticed the accumulation in lysosomal intensity as well as and positional changes to lysosomes in VAPA/VAPB knockdown ARPE19 cells. Furthermore, we found that forcing lysosomal accumulation was sufficient to induce cellular senescence. Overall, these results suggest that the ER contact protects epithelial cells against cellular senescence potentially by regulating lysosome homeostasis.

For years, biomedical research has continued to investigate the cause of aging and tried to cure age- related pathologies. The concept of cellular senescence has provided another path toward understanding aging, but our goal is still far to go. Through this project, we wanted to focus on providing a step to understand cellular senescence at intracellular level. Though further experiments are required to connect the results, we hope to provide a backbone direction toward linking the role of ER membrane contact in cellular senescence.