Abstract
Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine/glycine-dependent creatine biosynthesis.
Highlights
While amino acids are the building blocks of proteins, different amino acids participate in a wide variety of biological processes
In order for mammalian cells to live and function, amino acids are required for protein synthesis and the generation of metabolic intermediates
An imbalance or deficiency of amino acids often triggers an “amino acid response” (AAR) to allow cells to adapt to their environment
Summary
While amino acids are the building blocks of proteins, different amino acids participate in a wide variety of biological processes. Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that senses amino acid availability to regulate cell growth and autophagy. Another important sensor is the GCN2 (general control nonderepressible 2) kinase that regulates protein translation initiation in amino acid–starved cells by detecting uncharged tRNAs. Another important sensor is the GCN2 (general control nonderepressible 2) kinase that regulates protein translation initiation in amino acid–starved cells by detecting uncharged tRNAs These two kinases are highly conserved from yeast to mammalian cells and play major roles in the control of protein translation, transcriptional programs, and regulation of adaptive responses during amino acid starvation. An amino acid response element (AARE) in the promoters of these genes allows for the coordinated transcriptional regulation [2]
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