Translational control of methionine and serine metabolic pathways underpin the paralog-specific phenotypes of Rpl22 ribosomal protein mutants in cell division and replicative longevity

Abstract

21A long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) 22 often display distinct phenotypes. Some may reflect general effects due to lower growth rate 23 and ribosome levels, but a number of diverse phenotypes cannot be explained through this 24 mechanism. Yeast and other organisms live longer when they lack specific ribosomal proteins, 25 especially of the large 60S subunit of the ribosome. However, longevity is neither associated 26 with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. 27Here, we comprehensively queried actively dividing RP paralog mutants through the cell cycle. 28Our data link transcriptional, translational, and metabolic changes to phenotypes associated 29 with the loss of paralogous RPs. We uncovered specific translational control of transcripts 30 encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) 31 pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites 32 associated with 1C metabolism. Loss of 1C enzymes, such as the serine 33 hydroxymethyltransferase Shm2p increased the longevity of wild type cells. These results 34 provide a molecular basis for paralog-specific phenotypes in ribosomal mutants and underscore 35 the significance of 1C metabolic pathways in mechanisms of cell division and cellular aging. 1C 36 pathways exist in all organisms, including humans, and targeting the relevant enzymes could 37 represent longevity interventions. 38Rpl22Ap does (He et al., 2014; Hoose et al., 2012;Truong et al., 2013). Dysregulation of 62 translation is also strongly linked with aging. The number of times a yeast cell can divide and 63 generate daughter cells defines its replicative lifespan (Steffen et al., 2009). Protein synthesis is 64 dysregulated in aged cells, and it is thought to be a driver of aging (Janssens et al., 2015). 65Mutations in ribosomal proteins of the large (60S) subunit constitute a significant class of pro-66 longevity mutations in yeast and other species (Kaeberlein and Kennedy, 2011; Kaeberlein et 67 al., 2005;McCormick et al., 2015;Steffen et al., 2008; Steffen et al., 2012). The rpl association 68 with longevity, however, is often paralog-specific and complex. For example, the Rpl22 double 69 paralog deletion is viable, but not long-lived (Steffen et al., 2012). The single rpl22aΔ mutants is 70 long-lived, but rpl22b∆ cells are not long-lived (Steffen et al., 2012). In other ribosomal proteins, 71 e.g., Rpl34, loss of either of the Rpl34 paralogs promotes longevity (Steffen et al., 2012). 72Importantly, bulk inhibition of translation with cycloheximide at various doses does not increase 73 lifespan (Steffen et al., 2008). The above observations argue that simple relations between 74 ribosome content, protein synthesis capacity, or generation time cannot sufficiently explain the 75 longevity of rpl paralog mutants. To account for these paralog-specific phenotypes, we decided 76 to identify patterns of translational ...

A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

“…These results suggest that perturbing flux through the onecarbon metabolism pathway under non-restricted conditions can influence long term cell survival, perhaps by forcing metabolism toward gluconeogenesis and the glyoxylate cycle, thus mimicking CR. Interestingly, yeast replicative lifespan extension caused by deletion of the RPL22A gene was recently shown to correlate with reduced translation of one-carbon metabolism enzymes (87). Furthermore, deleting genes involved in one-carbon metabolism moderately extended replicative lifespan, similar to what we observed for CLS.…”

A cell non-autonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

“…These results suggest that perturbing flux through the one-carbon metabolism pathway under non-restricted conditions can influence long term cell survival, perhaps by forcing metabolism toward gluconeogenesis and the glyoxylate cycle. Interestingly, yeast replicative lifespan extension caused by deletion of the RPL22A gene was recently shown to correlate with reduced translation of one-carbon metabolism enzymes (86). Furthermore, deleting genes involved in one-carbon metabolism moderately extended replicative lifespan, similar to what we observed for CLS.…”

Spatially Enriched Paralog Rearrangements Argue Functionally Diverse Ribosomes Arise during Cold Acclimation in Arabidopsis

“…The eL22 paralogs have effectively subfunctionalized in Drosophila [ 114 ]. Additionally, in yeast, paralog-specific phenotypes of eL22 are related to translational control of the serine and methionine metabolic pathways [ 115 ]. Thus, variations in eL22 paralogs can effectively produce functional divergence and may be used by plants to enhance the REIL-60S interaction.…”