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

Tavane D. Cambiaghi, Catia M. Pereira, Renuka Shanmugam, Michael Bolech, Ronald Wek, Evelyn Sattlegger, Beatriz A. Castilho

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

In response to a range of environmental stresses, phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2α) represses general protein synthesis coincident with increased translation of specific mRNAs, such as those encoding the transcription activators GCN4 and ATF4. The eIF2α 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 eIF2α 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, H2O 2 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 eIF2α kinase.

Original languageEnglish
Pages (from-to)592-597
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume443
Issue number2
DOIs
StatePublished - Jan 10 2014

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Phosphotransferases
Chemical activation
Prokaryotic Initiation Factor-2
Yeasts
Benomyl
Yeast
Amino Acids
Cells
Association reactions
Protein Biosynthesis
Proteasome Endopeptidase Complex
Starvation
Transfer RNA
Acetic Acid
Phosphorylation
Cell Survival
Cell growth
Proteins
Transcription
Nutrients

Keywords

  • eIF2
  • GCN1
  • GCN2
  • IMPACT
  • Translational regulation
  • YIH1

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2. / Cambiaghi, Tavane D.; Pereira, Catia M.; Shanmugam, Renuka; Bolech, Michael; Wek, Ronald; Sattlegger, Evelyn; Castilho, Beatriz A.

In: Biochemical and Biophysical Research Communications, Vol. 443, No. 2, 10.01.2014, p. 592-597.

Research output: Contribution to journalArticle

Cambiaghi, Tavane D. ; Pereira, Catia M. ; Shanmugam, Renuka ; Bolech, Michael ; Wek, Ronald ; Sattlegger, Evelyn ; Castilho, Beatriz A. / Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2. In: Biochemical and Biophysical Research Communications. 2014 ; Vol. 443, No. 2. pp. 592-597.
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