title: Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis.
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.
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Xiaohu
authors: X
authors: Tang
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Melissa M
authors: MM
authors: Keenan
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Jianli
authors: J
authors: Wu
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Chih-An
authors: CA
authors: Lin
authors: Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America; Duke Proteomics and Metabolomics Core Facility Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Laura
authors: L
authors: Dubois
authors: Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America; Duke Proteomics and Metabolomics Core Facility Duke University Medical Center, Durham, North Carolina, United States of America; Department of Pharmacology and Cancer Biology Duke University Medical Center, Durham, North Carolina, United States of America.
authors: J Will
authors: JW
authors: Thompson
authors: Department of Surgery Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Stephen J
authors: SJ
authors: Freedland
authors: Department of Surgery Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Susan K
authors: SK
authors: Murphy
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Jen-Tsan
authors: JT
authors: Chi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003401:Creatine / Q000096:biosynthesis*; D006801:Humans; D061986:MCF-7 Cells; D008715:Methionine / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D002352:Carrier Proteins; C486715:TXNIP protein, human; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4; D008715:Methionine; D003401:Creatine