瑞士诺华生物医学研究中心César Fernández和Benedikt Goretzki合作取得新进展。他们报道了互补型SCF类E3连接酶介导的双重BACH1调控。相关研究成果2024年12月9日在线发表于《细胞》杂志上。
据介绍，BACH1是细胞氧化应激反应的关键调节因子，也是一种癌基因，由两种不同的F-box泛素连接酶SCFFBXO22和SCFFBXL17进行严格的翻译后控制。然而，这两种连接酶如何在氧化应激下识别BACH1尚不清楚。
研究人员阐明了FBXO22如何识别，BACH1-BTB二聚体结构域交换β折叠中的四元降解基序的机制。与癌症相关的突变和半胱氨酸修饰，使降解基序不稳定并损害FBXO22结合，但同时暴露出二聚体界面中被屏蔽的降解基序，使FBXL17能够识别BACH1为单体。
这些发现揭示了一种连接酶开关机制，该机制能够通过互补连接酶对BACH1进行翻译后调节，这取决于其BTB结构域的稳定性。
总之，这一研究结果为氧化应激反应提供了机制上的见解，并可能促进针对氧化应激相关疾病和癌症的治疗方法。
附：英文原文
Title: Dual BACH1 regulation by complementary SCF-type E3 ligases
Author: Benedikt Goretzki, Maryam Khoshouei, Martin Schrder, Patrick Penner, Luca Egger, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Catrin Swantje Müller, Zacharias Thiel, Merve Mutlu, Claude Tschopp, David Furkert, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, Philipp Hoppe, Enrico Schmidt, Sascha Gutmann, Mario Iurlaro, Grigory Ryzhakov, César Fernández
Issue&Volume: 2024-12-09
Abstract: 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.
DOI: 10.1016/j.cell.2024.11.006
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01322-9