Distinct Perception Mechanisms of BACH1 Quaternary Structure Degrons by Two F-box Proteins under Oxidative Stress

  • bioRxiv. 2024 Jun 3:2024.06.03.594717. doi: 10.1101/2024.06.03.594717.
Shiyun Cao  1  2 ,  Huigang Shi  1  2 ,  Sheena Faye Garcia  3  4 ,  Yuki Kito  3  4 ,  Hui Shi  1  2 ,  Hailey V Goldberg  3  4 ,  Jackeline Ponce  3  4  5 ,  Beatrix Ueberheide  3  4  5 ,  Luca Lignitto  3  4  6 ,  Michele Pagano  3  4  7 ,  Ning Zheng  1  2  8
Affiliations
  • 1. Department of Pharmacology, Box 357280, University of Washington, Seattle, WA, USA.
  • 2. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
  • 3. Department of Biochemistry and Molecular Pharmacology.
  • 4. Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 5. Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 6. Cancer Research Center of Marseille (CRCM), CNRS, Aix Marseille Univ, INSERM, Institut Paoli-Calmettes, Marseille, France.
  • 7. Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 8. Lead contact.
PMID: 38895309 DOI: 10.1101/2024.06.03.594717
Abstract

The transcription factor BACH1 regulates heme homeostasis and oxidative stress responses and promotes Cancer metastasis upon aberrant accumulation. Its stability is controlled by two F-box protein ubiquitin ligases, FBXO22 and FBXL17. Here we show that the homodimeric BTB domain of BACH1 functions as a previously undescribed quaternary structure degron, which is deciphered by the two F-box proteins via distinct mechanisms. After BACH1 is released from chromatin by heme, FBXO22 asymmetrically recognizes a cross-protomer interface of the intact BACH1 BTB dimer, which is otherwise masked by the co-repressor NCOR1. If the BACH1 BTB dimer escapes the surveillance by FBXO22 due to oxidative modifications, its quaternary structure integrity is probed by a pair of FBXL17, which simultaneously engage and remodel the two BTB protomers into E3-bound monomers for ubiquitination. By unveiling the multifaceted regulatory mechanisms of BACH1 stability, our studies highlight the abilities of ubiquitin ligases to decode high-order protein assemblies and reveal therapeutic opportunities to block Cancer invasion via compound-induced BACH1 destabilization.

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