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A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity

Jessica Diring1, Barbara Camuzeaux, Mariel Donzeau

  • 1Université de Strasbourg, UMR7242 Biotechnologie et Signalisation Cellulaire, Ecole Supérieure de Biotechnologie de Strasbourg, BP10413, Illkirch, France.

Plos One
|August 23, 2011
PubMed

Insights

A newly identified ATF7-4 protein isoform acts as a cytoplasmic inhibitor, blocking the activation of ATF2 and ATF7 transcription factors by preventing key phosphorylation events.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The proteome's complexity arises from alternative splicing and post-translational modifications.
  • Activating transcription factors ATF2 and ATF7 are homologous nuclear proteins activated by stress and growth factors via sequential phosphorylation.
  • Mitogen-activated protein kinases (MAPKs) are key enzymes in the phosphorylation cascade that activates ATF2 and ATF7.

Purpose of the Study:

  • To identify and characterize a novel cytoplasmic alternatively spliced isoform of ATF7.
  • To elucidate the regulatory mechanism of this new isoform on ATF2 and ATF7 transcriptional activity.
  • To understand the role of this isoform in cellular signaling pathways.

Main Methods:

  • Identification and characterization of the ATF7-4 isoform.
  • Investigating the effect of ATF7-4 on ATF2 and ATF7 phosphorylation.
  • Analyzing the subcellular localization of ATF7-4 and its interaction with kinases.
  • Studying the ubiquitylation and degradation of ATF7-4 upon stimulation.

Main Results:

  • A cytoplasmic alternatively spliced variant of ATF7, named ATF7-4, was identified.
  • ATF7-4 inhibits ATF2 and ATF7 transcriptional activity by sequestering the Thr53-phosphorylating kinase in the cytoplasm, preventing initial phosphorylation.
  • Stimulus-induced phosphorylation of ATF7-4 leads to its poly-ubiquitylation and degradation, releasing the kinase and allowing ATF7/ATF2 activation.

Conclusions:

  • ATF7-4 functions as a critical cytoplasmic negative regulator of ATF7 and ATF2.
  • This regulatory mechanism involves kinase sequestration and stimulus-dependent degradation.
  • The discovery of ATF7-4 adds a new layer of complexity to the regulation of transcription factors involved in stress and growth responses.

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