Astrin limits mTORC1 activity and prevents apoptosis under conditions of oxidative stress.
Major finding: Astrin limits mTORC1 activity and prevents apoptosis under conditions of oxidative stress.
Mechanism: Astrin recruits Raptor to stress granules, thereby preventing association of mTOR with Raptor.
Impact: Inhibition of Astrin may sensitize cancer cells to apoptosis induced by mTORC1 hyperactivation.
Hyperactivation of mTOR complex 1 (mTORC1) induces a negative feedback loop that suppresses AKT signaling and can trigger apoptosis. Oxidative stress has been suggested to activate mTORC1 signaling via downregulation of the negative regulatory proteins tuberous sclerosis complex 1 and 2 to promote translation of stress response proteins. Recent studies have implicated stress granules, which are induced by oxidative stress and sequester signaling molecules and mRNA, in the inhibition of mTOR signaling and protection from stress-induced cell death, but the mechanisms that restrict mTORC1 activation and prevent apoptosis remain unclear. Thedieck and colleagues found that Astrin, a protein involved in mitotic progression and highly expressed in cancer cells, specifically interacted with the mTORC1 component Raptor and impaired the association of mTOR with Raptor, suggesting that Astrin negatively regulates mTORC1 signaling. Indeed, Astrin depletion enhanced mTORC1 assembly and accelerated activation of ribosomal protein S6 kinase 1 and induction of mTORC1 negative feedback signaling independent of mitosis. In response to oxidative stress or other conditions that induced stress granules, Astrin colocalized with stress granule markers via its C-terminal coiled-coil domain and recruited Raptor to these granular structures via its N-terminal head domain, resulting in decreased mTOR–Raptor complex formation and suppression of mTORC1 activity. The inhibition of mTORC1 by Astrin was dependent on stress granules and protected cancer cells from apoptosis under oxidative stress; Astrin knockdown or inhibition of stress granules increased apoptosis, whereas mTORC1 blockade restored cell viability in Astrin-deficient cells, suggesting that Astrin suppresses apoptosis induced by mTORC1 hyperactivation in stressed cells. These findings identify a role for Astrin and stress granules in maintaining balanced mTORC1 signaling and preventing apoptosis under cellular stress and suggest that inhibition of Astrin may sensitize cancer cells to stress-induced cell death.