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Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma

Moritz Hentschke1, Uwe Borgmeyer

  • 1Zentrum für Molekulare Neurobiologie, Institut für Entwicklungsneurobiologie, Universität Hamburg, Martinistrasse 52, D-20246, Hamburg, Germany.

Biochemical and Biophysical Research Communications
|December 4, 2003
PubMed

Insights

Estrogen-related receptor gamma (ERRgamma) interacts with cofactors PNRC2 and TLE1. Unexpectedly, the corepressor TLE1 also acts as an ERRgamma coactivator, revealing new insights into nuclear receptor regulation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor crucial for metabolic and developmental processes.
  • ERRgamma is highly expressed in vital organs including the heart, skeletal muscle, kidney, and brain.
  • Understanding ERRgamma’s transcriptional regulation is key to deciphering its physiological roles.

Purpose of the Study:

  • To identify novel cofactors that interact with the activation function-1 (AF-1) domain of ERRgamma.
  • To investigate the role of these cofactors in modulating ERRgamma transcriptional activity.

Main Methods:

  • Utilized phage display biopanning to screen for human cDNAs binding to the AF-1 domain of ERRgamma.
  • Employed pull-down assays to confirm direct interactions between ERRgamma and identified proteins.
  • Conducted reporter gene assays to assess the functional impact of cofactors on ERRgamma activity.

Main Results:

  • Identified proline-rich nuclear receptor co-regulatory protein 2 (PNRC2) and the bHLH corepressor TLE1 as binding partners for ERRgamma's AF-1 domain.
  • Confirmed direct physical interactions between full-length PNRC2 and TLE1 with ERRgamma.
  • Demonstrated that both PNRC2 and TLE1 function as coactivators for ERRgamma in reporter gene assays, with TLE1's coactivator role being a novel finding.

Conclusions:

  • PNRC2 and TLE1 are direct interaction partners of ERRgamma.
  • TLE1, a known corepressor, unexpectedly acts as a coactivator for ERRgamma, expanding the understanding of its regulatory functions.
  • These findings highlight the complex mechanisms of nuclear receptor transcriptional control and identify new potential targets for therapeutic intervention.

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