Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2

Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2

Author Cambiaghi, Tavane D. Autor UNIFESP Google Scholar
Pereira, Catia M. Autor UNIFESP Google Scholar
Shanmugam, Renuka Google Scholar
Bolech, Michael Google Scholar
Wek, Ronald C. Google Scholar
Sattlegger, Evelyn Google Scholar
Castilho, Beatriz A. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Massey Univ
Indiana Univ
Abstract In response to a range of environmental stresses, phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2 alpha) represses general protein synthesis coincident with increased translation of specific mRNAs, such as those encoding the transcription activators GCN4 and ATF4. the eIF2 alpha kinase GCN2 is activated by amino acid starvation by a mechanism involving GCN2 binding to an activator protein GCN1, along with association with uncharged tRNA that accumulates during nutrient deprivation. We previously showed that mammalian IMPACT and its yeast ortholog YIH1 bind to GCN1, thereby preventing GCN1 association with GCN2 and stimulation of this eIF2 alpha, kinase during amino acid depletion. GCN2 activity is also enhanced by other stresses, including proteasome inhibition, UV irradiation and lack of glucose. Here, we provide evidence that IMPACT affects directly and specifically the activation of GCN2 under these stress conditions in mammalian cells. We show that activation of mammalian GCN2 requires its interaction with GCN1 and that IMPACT promotes the dissolution of the GCN2-GCN1 complex. To a similar extent as the overexpression of YIH1, overexpression of IMPACT in yeast cells inhibited growth under all stress conditions that require GCN2 and GCN1 for cell survival, including exposure to acetic acid, high levels of NaCl, H2O2 or benomyl. This study extends our understanding of the roles played by GCN1 in GCN2 activation induced by a variety of stress arrangements and suggests that IMPACT and YIH1 use similar mechanisms for regulating this eIF2 alpha kinase. (C) 2013 Elsevier Inc. All rights reserved.
Keywords Translational regulation
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Auckland Medical Research Foundation
Maurice & Phyllis Paykel Trust
Health Research Council
Massey University
New Zealand Lottery Health Research PhD scholarship
Date 2014-01-10
Published in Biochemical and Biophysical Research Communications. San Diego: Academic Press Inc Elsevier Science, v. 443, n. 2, p. 592-597, 2014.
ISSN 0006-291X (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 592-597
Origin http://dx.doi.org/10.1016/j.bbrc.2013.12.021
Access rights Closed access
Type Article
Web of Science ID WOS:000331162900041
URI http://repositorio.unifesp.br/handle/11600/37312

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