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ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase

I Lassot1, E Ségéral, C Berlioz-Torrent

  • 1INSERM Unite 529, Interactions Moléculaires Hôte-pathogène, 75014 Paris, France.

Molecular and Cellular Biology
|March 10, 2001
PubMed

Insights

The SCF(betaTrCP) E3 ubiquitin ligase targets the ATF4 transcription factor for degradation. This discovery reveals a new mechanism controlling bZIP transcription factor stability and gene expression.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Ubiquitin-Proteasome System

Background:

  • The ubiquitin-proteasome pathway is crucial for regulating gene expression via protein degradation.
  • The SCF(betaTrCP) E3 ubiquitin ligase targets key proteins like IkappaBalpha and beta-catenin.
  • ATF4 is a transcription factor belonging to the ATF-CREB bZIP family.

Purpose of the Study:

  • To investigate the role of the F-box protein betaTrCP in the regulation of ATF4 stability.
  • To identify the E3 ubiquitin ligase responsible for ATF4 degradation.
  • To elucidate the mechanism of ATF4 ubiquitination and degradation.

Main Methods:

  • Co-localization studies of betaTrCP and ATF4 in the nucleus.
  • Analysis of ATF4 phosphorylation and specific serine residues (e.g., Serine 219).
  • Assessment of ATF4 ubiquitination and degradation in HeLa cells with varying betaTrCP expression.

Main Results:

  • BetaTrCP and ATF4 were found to co-localize in the nucleus.
  • ATF4 stability is controlled by betaTrCP through a phosphorylation-dependent mechanism involving Serine 219.
  • ATF4 ubiquitination is enhanced by betaTrCP, leading to its degradation.
  • A dominant-negative mutant of betaTrCP inhibited ATF4 degradation and enhanced its transcriptional activity.

Conclusions:

  • ATF4 is a novel substrate for the SCF(betaTrCP) E3 ubiquitin ligase complex.
  • This study identifies the first mammalian E3 ubiquitin ligase controlling the degradation of a bZIP transcription factor.
  • The SCF(betaTrCP)-ATF4 interaction provides a new regulatory mechanism for gene expression.

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