2. Academic Validation
  3. Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress

Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress

  • Cell. 2024 Oct 30:S0092-8674(24)01188-7. doi: 10.1016/j.cell.2024.10.012.
Shiyun Cao 1,  Sheena Faye Garcia 2,  Huigang Shi 1,  Ellie I James 3,  Yuki Kito 2,  Hui Shi 1,  Haibin Mao 1,  Sharon Kaisari 2,  Gergely Rona 4,  Sophia Deng 2,  Hailey V Goldberg 2,  Jackeline Ponce 5,  Beatrix Ueberheide 5,  Luca Lignitto 6,  Miklos Guttman 3,  Michele Pagano 7,  Ning Zheng 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  • 2 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 3 Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; Molecular Engineering & Science Institute, University of Washington, Seattle, WA 98195, USA.
  • 4 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA; Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
  • 5 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 6 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Cancer Research Center of Marseille (CRCM), CNRS, Aix Marseille University, INSERM, Institut Paoli-Calmettes, Marseille, France.
  • 7 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.
  • 8 Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: nzheng@uw.edu.
PMID: 39504958 DOI: 10.1016/j.cell.2024.10.012
Abstract

Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 Ligases to decode the targets' degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.

Keywords

BACH1; BTB; FBXL17; FBXO22; SCF; cullin-RING ligases; degron; dimer; heme; nitric oxide; oxidative stress; protein degradation; quaternary structure; transcription factor; ubiquitin ligase.

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