Stress granules counteract senescence by sequestration of PAI‐1

Abstract

Cellular senescence is a physiological response by which an organism halts the proliferation of potentially harmful and damaged cells. However, the accumulation of senescent cells over time can become deleterious leading to diseases and physiological decline. Our data reveal a novel interplay between senescence and the stress response that affects both the progression of senescence and the behavior of senescent cells. We show that constitutive exposure to stress induces the formation of stress granules (SGs) in proliferative and presenescent cells, but not in fully senescent cells. Stress granule assembly alone is sufficient to decrease the number of senescent cells without affecting the expression of bona fide senescence markers. SG‐mediated inhibition of senescence is associated with the recruitment of the plasminogen activator inhibitor‐1 (PAI‐1), a known promoter of senescence, to these entities. PAI‐1 localization to SGs increases the translocation of cyclin D1 to the nucleus, promotes RB phosphorylation, and maintains a proliferative, non‐senescent state. Together, our data indicate that SGs may be targets of intervention to modulate senescence in order to impair or prevent its deleterious effects.

The molecular language of membraneless organelles

“…Results in yeast also extend to mammalian cells, where stress-induced stalling of translation leads to the condensation of protein and RNA into stress granules, which are dissolved after stress by Hsp110, Hsp70, and Hsp40 (8,75). Importantly, stress granules protect against cellular senescence by sequestering PAI-1, an established promoter of senescence (76). Overall, the ability of cells to form assemblages of proteins and nucleic acids in response to stress appears to be a conserved mechanism for cells to weather deleterious conditions.…”

The involvement of stress granules in aging and aging‐associated diseases

“…These results indicate that when cells enter the senescence state, two essential SG proteins, eIF2α and the transcription factor Sp1, can work as direct aging‐related targets, causing significant deficiencies in SG production. Similarly, a recent study found that constitutive exposure to stress could induce the formation of SGs in proliferating cells, but not in fully senescent human fibroblasts (Omer et al, 2018). It has also been reported that the formation of SGs during early stages of senescence is sufficient to prevent senescence.…”

“…Plasminogen activator inhibitor‐1 (PAI‐1), an activator of senescence, is also localized to SGs in senescent cells. This indicates that SGs can counteract senescence by recruiting a key factor to the SGs and disrupting its senescence function (Omer et al, 2018).…”

“…This process involves the recruitment of PAI‐1 to the SGs. Recruitment of PAI‐1 to SGs interferes with secretion of PAI‐1 and, consequently, cytoplasmic retention of cyclin D1, which further promotes the phosphorylation of pRB, leading to the prevention of cell cycle arrest (Omer et al, 2018). Thus, as SGs can regulate genes that play important roles in senescence, SGs could function as a target of intervention to modulate the senescence process.…”

“…Lian et al found that senescent cells are able to form SGs under acute stress, and the number of SGs significantly increases, compared with nonsenescent cells (Lian & Gallouzi, 2009). This increase correlates with a rapid decrease in the expression levels of the senescence‐associated gene, p21 (Lian & Gallouzi, 2009), which is not found in senescent cells under chronic and persistent stress (Omer et al, 2018). This suggests that how senescence process and the behavior of senescent cells respond to stress might depend on the method used to induce stress and whether or not the stress is physiologically relevant.…”