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, SCFFBXO22 and SCFFBXL17. 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. [Display omitted] •BACH1 protein stability is regulated by SCFFBXO22 and SCFFBXL17 E3 ligases•FBXO22 recognizes dimeric BACH1 through a quaternary degron in its BTB domain•Cancer-related mutations and cysteine modifications perturb the quaternary degron•Loss of degron and BTB stability enables FBXL17 to recognize BACH1 as a monomer The transcription factor BACH1 is regulated by two distinct E3 ligases, SCFFBXO22 and SCFFBXL17, through complementary degrons in its BTB domain that enable differentiation between its native and destabilized dimeric forms.