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

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

Autor Pereira, Catia Mendes Autor UNIFESP Google Scholar
Sattlegger, E. Google Scholar
Jiang, H. Y. Google Scholar
Longo, Beatriz Monteiro Autor UNIFESP Google Scholar
Jaqueta, Carolina de Barros Autor UNIFESP Google Scholar
Hinnebusch, A. G. Google Scholar
Wek, R. C. Google Scholar
Mello, Luiz Eugenio Araujo de Moraes Autor UNIFESP Google Scholar
Castilho, Beatriz Amaral de Autor UNIFESP Google Scholar
Instituição Universidade Federal de São Paulo (UNIFESP)
NICHD
Indiana Univ
Resumo Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2 alpha) 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 eIF2 alpha, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2 alpha 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 eIF2 alpha 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.
Idioma Inglês
Data de publicação 2005-08-05
Publicado em Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 280, n. 31, p. 28316-28323, 2005.
ISSN 0021-9258 (Sherpa/Romeo, fator de impacto)
Publicador Amer Soc Biochemistry Molecular Biology Inc
Extensão 28316-28323
Fonte http://dx.doi.org/10.1074/jbc.M408571200
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000230857300018
Endereço permanente http://repositorio.unifesp.br/handle/11600/28422

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