Dual BACH1 regulation by complementary SCF-type E3 ligases

Highlights

•BACH1 protein stability is regulated by SCF^FBXO22 and SCF^FBXL17 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

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^FBXO22 and SCF^FBXL17. 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.

Broad-complex、tramtrack 和 bric-à-brac 结构域 （BTB） 和 CNC 同源物 1 （BACH1） 是细胞氧化应激反应的关键调节因子，也是一种癌基因，它受到两种不同的 F-box 泛素连接酶 SCF 的严格翻译后控制^FBXO22和 SCF^{FBXL17 系列}.然而，两种连接酶如何在氧化应激下识别 BACH1 尚不清楚。在我们的研究中，我们阐明了 FBXO22 识别 BACH1 BTB 二聚体结构域交换β片中的四元 degron 的机制。癌症相关突变和半胱氨酸修饰会破坏 degron 的稳定性并损害 FBXO22 结合，但同时在二聚体界面中暴露出原本被屏蔽的 degron，使 FBXL17 能够将 BACH1 识别为单体。这些发现揭示了一种连接酶转换机制，该机制能够根据其 BTB 结构域的稳定性通过互补连接酶对 BACH1 进行翻译后调节。我们的结果为氧化应激反应提供了机制见解，并可能激发针对氧化应激相关疾病和癌症的治疗方法。