The σS subunit of RNA polymerase is a master regulator of Escherichia coli that retards cellular senescence and bestows cells with general stress protective functions during growth arrest. We show that mutations and drugs triggering translational errors elevate σS levels and stability. Furthermore, mutations enhancing translational fidelity attenuate induction of the rpoS regulon and prevent stabilization of σS upon carbon starvation. Destabilization of σS by increased proofreading requires the presence of the σS recognition factor SprE (RssB) and the ClpXP protease. The data further suggest that σS becomes stabilized upon starvation as a result of ClpP sequestration and this sequestration is enhanced by oxidative modifications of aberrant proteins produced by erroneous translation. ClpP overproduction counteracted starvation-induced stabilization of σS, whereas overproduction of a ClpXP substrate (ssrA-tagged GFP) stabilized σS in exponentially growing cells. We present a model for the sequence of events leading to the accumulation and activation of σS upon carbon starvation, which are linked to alterations in both ribosomal fidelity and efficiency.