The cellular demand for protein synthesis influences the ribosome maintenance program in vivo

Control of protein homeostasis is fundamental to the health and longevity of all organisms. Because the rate of protein synthesis by ribosomes is a central control point in this process, regulation and maintenance of ribosome function could have amplified importance in the overall regulatory circuit. Indeed, ribosomal defects are commonly associated with loss of protein homeostasis, aging and disease, whereas improved protein homeostasis, implying optimal ribosomal function, is associated with disease resistance and increased lifespan. To maintain a high quality ribosome population within the cell, dysfunctional ribosomes are targeted for autophagic degradation. It is not known if complete degradation is the only mechanism for eukaryotic ribosome maintenance or if they might also be repaired by replacement of defective components. We used stable‐isotope feeding and protein mass‐spectrometry to measure the kinetics of turnover of ribosomal RNA (rRNA) and 71 ribosomal proteins (r‐proteins) in assembled ribosomes as well as the turnover rates of ~1000 proteins in mouse liver. In general, peripheral r‐proteins and those with more direct roles in peptide‐bond formation are replaced multiple times during the lifespan of the assembled structure, presumably by exchange with a free cytoplasmic pool, whereas the majority of r‐proteins are stably incorporated for the lifetime of the ribosome. Dietary signals impact the general ribosome activity, rates of new ribosome assembly, and component r‐protein exchange. The results indicate that changes in ribosome activity are accompanied by variations in in vivo maintenance mechanisms ( Figure). Signal‐specific modulation of ribosomal repair and degradation could provide a mechanistic link in the frequently observed associations between diminished rates of protein synthesis, increased autophagy, and greater longevity. Support or Funding Information BYU startup funding, Fritz B. Burns Foundation In vivo ribosome maintenance requires ribophagy and r‐protein exchangeWe propose that during the lifetime of the assembled ribosomal structure, ribosome protein exchange occurs primarily when the ribosome disassociates to its individual subunits. This exchange may be a fast, low cost, method to repair and modify ribosomes. In mouse tissue cellular energetics and demand for protein synthesis modulate the relative contribution of ribophagy, versus exchange, to maintain high quality ribosomes.