Epistatic interaction between ribosome-associated Era GTPase and stringent response regulator RelA modulates bacterial cell growth and dormancy

Abstract

Cellular homeostasis is sustained by balancing the cell growth and quiescence in response to specific environmental cues. While the mechanisms governing the transition from growth to dormancy are reasonably well understood, the processes underlying exit from dormancy remain poorly characterised. Using an integrated approach employing bacterial genetics, Cryo-EM, and molecular microbiology, we investigated this phenomenon by studying the cross-talk between two antagonistic pathways, ribosome biogenesis that promotes cell growth, and stringent response that induces dormancy. We show that the exit from dormancy requires a conserved Era GTPase whose synthesis selectively rises during onset of exponential growth phase in Escherichia coli. Era not only accelerates the maturation of head and platform regions of 30S ribosomal subunit but also dislodges RelA from 70S ribosome. This derepresses the 70S ribosome from RelA-mediated inhibition, and promotes protein synthesis driving the active cell growth. This study uncovers that temporal epistatic interaction between Era and RelA governs cellular resuscitation in bacteria. Given that the dormant bacterial populations contribute to antibiotic tolerance, understanding this regulatory axis offers new insights for resensitising the recalcitrant dormant bacteria to antibiotics.