Translational control of one-carbon metabolism underpins ribosomal protein phenotypes in cell division and longevity.

Nairita Maitra,Birgit Schilling,Chong He,Mitsuhiro Tsuchiya,Rodolfo Aramayo,Michael Polymenis,Matt Kaeberlein,Brian K Kennedy,Heidi M Blank

doi:10.7554/elife.53127

Abstract

A long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) often display distinct phenotypes. Yeast and other organisms live longer when they lack specific ribosomal proteins, especially of the large 60S subunit of the ribosome. However, longevity is neither associated with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. Here, we queried actively dividing RP mutants through the cell cycle. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of paralogous RPs. We uncovered translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes increased the longevity of wild type cells. 1C pathways exist in all organisms and targeting the relevant enzymes could represent longevity interventions.

Highlights

Mutations in ribosomal proteins (RPs) often have distinct phenotypes and, in people, they lead to diseases called ribosomopathies (Aspesi and Ellis, 2019; De Keersmaecker et al, 2015; Goudarzi and Lindstrom, 2016; Mills and Green, 2017)
A weak, positive association had been reported between the change in mean lifespan in rpl mutants and their generation time relative to wild type cells (Steffen et al, 2008)
We found no significant association between the lifespan of rpl mutants with either their generation time (r = À0.02, based on the nonparametric, Spearman rank correlation coefficient), or the levels of the corresponding Rpl protein in wild type cells (r = À0.06; Figure 1 and Figure 1—source data 1)

Summary

Introduction

Mutations in ribosomal proteins (RPs) often have distinct phenotypes and, in people, they lead to diseases called ribosomopathies (Aspesi and Ellis, 2019; De Keersmaecker et al, 2015; Goudarzi and Lindstrom, 2016; Mills and Green, 2017). Specialized ribosomes with different composition may account for the distinct phenotypes of ribosomal protein mutants (Shi et al, 2017; Xue and Barna, 2012). In another scenario, in Diamond-Blackfan anemia patients carrying mutations in several ribosomal proteins, a lower ribosome content alters the translation of mRNAs critical for hematopoiesis (Khajuria et al, 2018). To understand how ribosomal protein mutants have distinct phenotypes, it is necessary to identify the relevant mRNAs with altered translational control, and link the corresponding gene products to the observed phenotypes

Methods

Results

Conclusion