IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation.
Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2alpha) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation. The GCN2 stress response, conserved from yeast to mammals, is critical for resistance to nutritional deficiencies and for the control of feeding behaviors in rodents. The mouse protein IMPACT has sequence similarities to the yeast YIH1 protein, an inhibitor of GCN2. YIH1 competes with GCN2 for binding to a positive regulator, GCN1. Here, we present evidence that IMPACT is the functional counterpart of YIH1. Overexpression of IMPACT in yeast lowered both basal and amino acid starvation-induced levels of phosphorylated eIF2alpha, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2alpha by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153). IMPACT bound to the minimal yeast GCN1 segment required for interaction with yeast GCN2 and YIH1 and to native mouse GCN1. At the protein level, IMPACT was detected mainly in the brain. IMPACT was found to be abundant in the majority of hypothalamic neurons. Scattered neurons expressing this protein at higher levels were detected in other regions such as the hippocampus and piriform cortex. The abundance of IMPACT correlated inversely with phosphorylated eIF2alpha levels in different brain areas. These results suggest that IMPACT ensures constant high levels of translation and low levels of ATF4 and CHOP in specific neuronal cells under amino acid starvation conditions.
Pereira
Cátia M
CM
Departamentos de Microbiologia, Imunologia, e Parasitologia and Fisiologia, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil.
Sattlegger
Evelyn
E
Jiang
Hao-Yuan
HY
Longo
Beatriz M
BM
Jaqueta
Carolina B
CB
Hinnebusch
Alan G
AG
Wek
Ronald C
RC
Mello
Luiz E A M
LE
Castilho
Beatriz A
BA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010445:Peptide Elongation Factors; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators
D002352:Carrier Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C501389:GCN1 protein, S cerevisiae; C504444:GCN1 protein, mouse; C107747:Impact protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D010445:Peptide Elongation Factors; D011506:Proteins; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; C488521:YIH1 protein, S cerevisiae; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; C512912:GCN2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases