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Using In Vitro Fluorescence Resonance Energy Transfer to Study the Dynamics Of Protein Complexes at a Millisecond Time Scale
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NFE2L1/Nrf1 forms a coactivator complex post-peptide:N-glycanase-mediated sequence editing and mitigates proteasome

Yukiko Yoshida1, Meari Okada1, Naoko Arai1

  • 1Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|December 30, 2025
PubMed
Summary

Nuclear factor erythroid 2-like 1 (Nrf1) is activated by sequence editing, a unique process for transcription factors. This editing is crucial for proteasome gene expression and cell survival, but its constitutive activation can be toxic.

Keywords:
HCFC1NFE2L1NGLY1Nrf1proteasome

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Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-like 1 (NFE2L1/Nrf1) is an ER-associated transcription factor regulating proteasome genes.
  • Nrf1 is unique as it undergoes sequence editing for transcriptional activation, a process involving peptide:N-glycanase (NGLY1).

Purpose of the Study:

  • To elucidate the mechanism by which sequence editing regulates Nrf1's transcriptional activity.
  • To investigate the role of N-glycosylation site editing in Nrf1's function and cellular response.

Main Methods:

  • Studied sequence editing of N-glycosylation sites in human Nrf1 in HeLa cells.
  • Investigated protein interactions and chromatin binding of Nrf1.
  • Analyzed the impact of Nrf1 mutants on cell growth.

Main Results:

  • Sequence editing of Nrf1's Asn574 site is essential for proteasome gene expression and interaction with host cell factor C1 and O-GlcNAc transferase.
  • Editing of other N-glycosylation sites facilitates coactivator CREBBP/EP300 interaction, enhancing transcriptional activity.
  • Constitutive activation of Nrf1 via mimicking proteolytic processing or NGLY1 editing reduced cell growth, indicating cytotoxicity.

Conclusions:

  • Nrf1 activation is a regulated, on-demand process crucial for cellular survival during proteasomal stress.
  • Sequence editing of Nrf1 is a key regulatory mechanism controlling its transcriptional activity and interaction with coactivator complexes.
  • Uncontrolled Nrf1 activation can lead to cytotoxicity, highlighting the importance of its regulated expression.