Dual BACH1 regulation by complementary SCF-type E3 ligases

Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCF and SCF . However, how both ligases recognize BAC...

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Published in:Cell Vol. 187; no. 26; p. 7585
Main Authors: Goretzki, Benedikt, Khoshouei, Maryam, Schröder, Martin, Penner, Patrick, Egger, Luca, Stephan, Christine, Argoti, Dayana, Dierlamm, Nele, Rada, Jimena Maria, Kapps, Sandra, Müller, Catrin Swantje, Thiel, Zacharias, Mutlu, Merve, Tschopp, Claude, Furkert, David, Freuler, Felix, Haenni, Simon, Tenaillon, Laurent, Knapp, Britta, Hinniger, Alexandra, Hoppe, Philipp, Schmidt, Enrico, Gutmann, Sascha, Iurlaro, Mario, Ryzhakov, Grigory, Fernández, César
Format: Journal Article
Language:English
Published: United States 26.12.2024
Subjects:
Animals
Basic-Leucine Zipper Transcription Factors - genetics
Basic-Leucine Zipper Transcription Factors - metabolism
F-Box Proteins - chemistry
F-Box Proteins - metabolism
HEK293 Cells
Humans
Models, Molecular
Oxidative Stress
SKP Cullin F-Box Protein Ligases - metabolism
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Cullin-RING ligases
S-nitrosylation heme
F-box
cysteine modification
FBXL17
ligase switch
BACH1
FBXO22
oxidative stress
ISSN:1097-4172, 1097-4172
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Summary:Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCF and SCF . However, how both ligases recognize BACH1 under oxidative stress is unclear. In our study, we elucidate the mechanism by which FBXO22 recognizes a quaternary degron in a domain-swapped β-sheet of the BACH1 BTB dimer. Cancer-associated mutations and cysteine modifications destabilize the degron and impair FBXO22 binding but simultaneously expose an otherwise shielded degron in the dimer interface, allowing FBXL17 to recognize BACH1 as a monomer. These findings shed light on a ligase switch mechanism that enables post-translational regulation of BACH1 by complementary ligases depending on the stability of its BTB domain. Our results provide mechanistic insights into the oxidative stress response and may spur therapeutic approaches for targeting oxidative stress-related disorders and cancer.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2024.11.006