Editors' ChoiceCellular Metabolism

Centered on SAM

Sci. Signal.  23 Jul 2013:
Vol. 6, Issue 285, pp. ec170
DOI: 10.1126/scisignal.2004536

Cellular metabolism is tightly controlled by nutrient status. During periods of nutrient deprivation, cells limit anabolic processes and increase autophagy to reclaim nutrients. A pair of papers from the Tu laboratory defines biochemical pathways involving protein methylation and tRNA thiolation, which are both dependent on S-adenosylmethioine (SAM), and shows that yeast use these pathways to respond to deficiency in sulfur-containing amino acids. When yeast are transferred from rich medium to a minimal medium that is not limited in nitrogen, the cells initiate non–nitrogen-starvation-induced (NNS) autophagy. Sutter et al. showed that including methioinine in the minimal medium prevented NNS autophagy. SAM is generated from methionine, and both SAM and methionine abundance decreased when the cells were switched to minimal medium. SAM is used as a methyl donor for protein methylation, and the ability of methionine to inhibit NNS autophagy required the methyltransferase Ppm1p and the methylation of one of its targets, the catalytic subunit of the phosphatase PP2A. NNS autophagy involves the formation of a complex of Iml1p, Npr2p, and Npr3p, and phosphorylation of Npr2p promotes the formation of this complex. Phosphorylated Npr2p increased in cells switched to minimal medium, an increase that was prevented by methionine. Thus, yeast use methionine status as a regulator of the formation of an autophagic complex. In the second paper, Laxman et al. describe a pathway through which reactions involving SAM control the extent of a tRNA modification, uridine thiolation, which enhances the ability of tRNAs to “wobble” and read more than one codon. By mass spectrometry, the abundance of thiolated uridine was less in cells grown in minimal medium than in cells grown in rich medium or in minimal medium that included cysteine or methionine. The abundance of two proteins involved in tRNA thiolation, Urm1p and Uba4p, decreased when cells were switched to minimal medium, and this was prevented by including methionine in the medium. Genome-wide codon usage analysis revealed that genes enriched in the “wobble”-encoded amino acids, Lys, Glu, and Gln, were associated with rRNA processing, ribosome biogenesis, and translation. Analysis of an arbitrarily selected set of Lys- or Gln-rich proteins in wild-type or uba4-knockout cells showed that the abundance of these proteins was reduced in the knockout cells, suggesting that the tRNA thiolation promotes optimal translation of these transcripts. Although tRNA thiolation provided cells with a proliferative growth advantage, thiolation-deficient cells exhibited increased life span in a specific test for the ability to form colonies after growth to exhaustion in culture compared with wild-type cells. Thus, cells sense the abundance of methioinine, which as the precursor for SAM functions in both regulating autophagy (through protein methylation) and translation (through tRNA thiolation).

B. M. Sutter, X. Wu, S. Laxman, B. P. Tu, Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154, 403–415 (2013). [Online Journal]

S. Laxman, B. M. Sutter, X. Wu, S. Kumar, X. Guo, D. C. Trudgian, H. Mirzaei, B. P. Tu, Sulfur amino acids regulate translational capacity and metabolic homeostasis through modulation of tRNA thiolation. Cell 154, 416–429 (2013). [Online Journal]