Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt.

Translation is made of initiation, elongation, and termination. The role of termination in relaying extracellular outputs to the translation machinery is unknown. We show, in mice, that the controlled recycling of ribosomes post-termination is a major checkpoint that integrates mitogenic signals and antiviral responses. In detail, the recycling of ribosomes at stop codons, maximal translation, and cellular proliferation strictly depend on eIF6 phosphorylation, both in vitro and in vivo. Lack of eIF6 phosphorylation, as observed during viral infection or prolonged starving, causes accumulation of ribosomes at stop codons and a massive translational remodeling. The outcome is a cellular status that we named RESt, for reversible energetic stop. RESt is marked by pro-survival and pro-inflammatory NF-κB signaling and a switch to respiration. Acute RESt is rescued by eIF6 phosphorylation, but chronic RESt in vivo leads to senescence. Thus, the recycling rate of ribosomes post-termination is a physiologically controlled event impacting initiation.