Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress
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.
Authors
- Gergely Róna (ORCID: https://orcid.org/0000-0003-3222-7261)
- Luca Lignitto (ORCID: https://orcid.org/0000-0001-6164-1299)
- Hui Shi (ORCID: https://orcid.org/0000-0002-2027-723X)
- Miklós Guttman (ORCID: https://orcid.org/0000-0003-2419-1334)
- Jackeline Ponce (ORCID: https://orcid.org/0000-0002-3886-9989)
- Michele Pagano (ORCID: https://orcid.org/0000-0003-3210-2442)
- Beatrix Ueberheide (ORCID: https://orcid.org/0000-0003-2512-0204)
- Haibin Mao (ORCID: https://orcid.org/0000-0002-7233-9105)
- Ning Zheng (ORCID: https://orcid.org/0000-0002-1039-1581)
- Su-Jun Deng
- Sharon Kaisari (ORCID: https://orcid.org/0000-0002-6884-3886)
- Sheena Faye Garcia (ORCID: https://orcid.org/0000-0002-2716-2638)
- Shiyun Cao (ORCID: https://orcid.org/0000-0003-1201-4963)
- Hailey V. Goldberg (ORCID: https://orcid.org/0000-0002-4830-5626)
- Ellie I. James (ORCID: https://orcid.org/0000-0001-6737-948X)
- Yuki Kito
- Huigang Shi
Institutions
- Centre National de la Recherche Scientifique (FR)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- University of Washington (US)
- Aix-Marseille Université (FR)
- University of Washington Medical Center (US)
- Centre de Recherche en Cancérologie de Marseille (FR)
- New York University (US)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Cell
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1016/j.cell.2024.10.012
- Citations
- 24
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 5.61
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- University of Washington
- National Institutes of Health
- School of Medicine, New York University
- National Cancer Institute
- National Institute of General Medical Sciences