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J. Biol. Chem., Vol. 280, Issue 31, 28316-28323, August 5, 2005

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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 C. Wek**, Luiz E. A. M. Mello¶¶, and Beatriz A. Castilho||||

From the Departamentos de Microbiologia, Imunologia, e Parasitologia and Fisiologia, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil, the ^¶Laboratory of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2427, and the ^**Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Translational control directed by the eukaryotic translation initiation factor 2 -subunit (eIF2) 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, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2 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 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.

Received for publication, July 28, 2004 , and in revised form, May 31, 2005.

^* This work was supported in part by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (to B. A. C. and L. E. A. M. M.) and by National Institutes of Health Grant GM49164 (to R. C. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a postdoctoral fellowship from FAPESP.

^|| Present address: Inst. of Molecular BioSciences, Massey University, Albany, Auckland 1311, New Zealand.

Recipient of a postdoctoral fellowship from FAPESP. Present address: CPqGM-Fundaçao Oswaldo Cruz, 40296-710 Salvador, Bahia, Brazil.

^¶¶ Supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnológico.

^|||| Supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnológico. To whom correspondence should be addressed: Dept. Microbiologia, Imunologia, e Parasitologia, Universidade Federal de São Paulo, Rua Botucatu, 862, São Paulo SP 04023-062, Brazil. Tel.: 55-11-5576-4537; Fax: 55-11-5572-4711; E-mail: bac{at}ecb.epm.br.

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