Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

•Rheb suppresses protein synthesis in vitro and in vivo•Rheb induces phosphorylation of eIF2α independent of mTORC1•Rheb binds directly to PERK and increases its activity in vitro

SummaryRheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress, the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK). Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses.

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