mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Abstract

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response but it can also display pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find novel SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2/MAPKAPK2 kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells both in tumour-suppressive and promoting-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

“…For example, studies by Herranz et al . (2015) and Laberge et al . (2015) have shown that inhibition of mTOR by rapamycin selectively inhibits the SASP and SA β‐gal staining of senescent cells without affecting their cell cycle arrest.…”

“…Inhibition of the SASP probably requires activation of MAPKAPK2, which would explain the decrease in pro‐inflammatory cytokines. In fact, inhibition of MAPKAPK2 by rapamycin has been shown to decrease the levels of pro‐inflammatory cytokines including IL1α, and this effect is highly dependent on mTOR activity (Laberge et al ., 2015; Herranz et al ., 2015). However, we must to understand that the SASP can vary significantly in terms of the quantity and quality of secreted proteins and other factors, depending on the insult used to trigger cell senescence (Maciel‐Baron et al ., 2016; Wiley et al ., 2016); therefore, the composition of the SASP may be vary depending on the tissue and the insult.…”

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…The interplay between mitochondria and the mTOR signalling pathway may also be involved in this process, since we have shown that mitochondria clearance reduces mTOR activity and inhibition of mTOR activity inhibits proliferation contributing to quiescence. Recent studies have also shown that the mechanisms by which mTOR impacts on the cell cycle are uncoupled from its effect on the SASP (Herranz et al , 2015; Laberge et al , 2015). While we acknowledge that mitochondrial ablation is a drastic intervention with possible widespread consequences for the cells, our results demonstrate that mitochondria play a central role in many of the transcriptional changes observed during senescence, particularly the SASP, and have, as such, a great therapeutic potential.…”

“…While mTORC1 has previously been implicated in senescence (Pospelova et al , 2012), the mechanisms regulating its activation as well as its links to the pro‐oxidant and pro‐inflammatory features of the phenotype are still unclear. Two recent studies have shown that mTOR inhibition suppressed the senescence‐associated secretion of inflammatory cytokines by suppressing the translation of SASP regulatory proteins IL‐1A and MK2 (Herranz et al , 2015; Laberge et al , 2015). On the other hand, our data show that interventions targeting the mTOR pathway affect the maintenance of a DDR via the generation of ROS, which has been shown to be necessary for the induction of senescence and the SASP (Rodier et al , 2009; Passos et al , 2010).…”

TORn about SASP regulation

“…1,2 However, the details and implications of this regulation have not been clarified until now. Two recent manuscripts, from Campisi and colleagues 3 and our group, 4 have proposed molecular mechanisms by which inhibition of mTOR suppresses the SASP.…”