IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation

Cátia M. Pereira, Evelyn Sattlegger, Hao Yuan Jiang, Beatriz M. Longo, Carolina B. Jaqueta, Alan G. Hinnebusch, Ronald Wek, Luiz E A M Mello, Beatriz A. Castilho

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Abstract

Translational control directed by the eukaryotic translation initiation factor 2 α-subunit (eIF2α) 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 eIF2α, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2α 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 eIF2α 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.

Original languageEnglish
Pages (from-to)28316-28323
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number31
DOIs
StatePublished - Aug 5 2005

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Prokaryotic Initiation Factor-2
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Yeast
Brain
Starvation
Yeasts
Chemical activation
Neurons
Proteins
Amino Acids
Phosphorylation
Mammals
Fungal Proteins
Feeding Behavior
Fibroblasts
Gene expression
Leucine
Malnutrition
Rodentia

ASJC Scopus subject areas

  • Biochemistry

Cite this

Pereira, C. M., Sattlegger, E., Jiang, H. Y., Longo, B. M., Jaqueta, C. B., Hinnebusch, A. G., ... Castilho, B. A. (2005). IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. Journal of Biological Chemistry, 280(31), 28316-28323. https://doi.org/10.1074/jbc.M408571200

IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. / Pereira, Cátia M.; Sattlegger, Evelyn; Jiang, Hao Yuan; Longo, Beatriz M.; Jaqueta, Carolina B.; Hinnebusch, Alan G.; Wek, Ronald; Mello, Luiz E A M; Castilho, Beatriz A.

In: Journal of Biological Chemistry, Vol. 280, No. 31, 05.08.2005, p. 28316-28323.

Research output: Contribution to journalArticle

Pereira, CM, Sattlegger, E, Jiang, HY, Longo, BM, Jaqueta, CB, Hinnebusch, AG, Wek, R, Mello, LEAM & Castilho, BA 2005, 'IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation', Journal of Biological Chemistry, vol. 280, no. 31, pp. 28316-28323. https://doi.org/10.1074/jbc.M408571200
Pereira CM, Sattlegger E, Jiang HY, Longo BM, Jaqueta CB, Hinnebusch AG et al. IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. Journal of Biological Chemistry. 2005 Aug 5;280(31):28316-28323. https://doi.org/10.1074/jbc.M408571200
Pereira, Cátia M. ; Sattlegger, Evelyn ; Jiang, Hao Yuan ; Longo, Beatriz M. ; Jaqueta, Carolina B. ; Hinnebusch, Alan G. ; Wek, Ronald ; Mello, Luiz E A M ; Castilho, Beatriz A. / IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 31. pp. 28316-28323.
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AU - Jaqueta, Carolina B.

AU - Hinnebusch, Alan G.

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