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Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover

Meng-Kwang Marcus Tan1, Hui-Jun Lim, Eric J Bennett

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|September 17, 2013
PubMed

Insights

Researchers developed a new proteomics method to identify E3 ubiquitin ligase substrates. This method revealed FBXL17 regulates the NRF2 oxidative stress pathway by controlling BACH1 turnover.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Proteomics

Background:

  • Modular cullin-RING E3 ubiquitin ligases (CRLs) utilize substrate adaptors to target proteins for ubiquitylation.
  • Identifying substrates for the numerous human CRL adaptor proteins is challenging due to limited efficient methods.

Purpose of the Study:

  • To develop and apply a novel proteomics technique for systematically identifying E3 ligase adaptor substrates.
  • To investigate the function of the F-box protein FBXL17 in the context of oxidative stress response.

Main Methods:

  • Development of parallel adaptor capture (PAC) proteomics.
  • Systematic identification of candidate substrates for leucine-rich repeat F-box proteins (FBXLs).
  • Validation of FBXL17's role in regulating the NRF2 pathway.

Main Results:

  • PAC proteomics enabled systematic substrate identification for SCF E3 ligases.
  • FBXL17 was identified as a novel regulator of the NRF2 oxidative stress pathway.
  • FBXL17 controls HMOX1 transcription through BACH1 degradation, impacting NRF2-dependent gene activation.

Conclusions:

  • The study introduces PAC proteomics as a powerful tool for CRL adaptor protein research.
  • Identified SCF(FBXL17) as a key regulator of the NRF2 pathway's activation threshold.
  • Provides a framework for future elucidation of CRL adaptor protein functions and substrate specificities.

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