美国华盛顿大学Ning Zheng等研究人员合作发现，氧化应激下两种F-box蛋白识别BACH1四级结构降解信号。相关论文于2024年11月5日在线发表在《细胞》杂志上。

研究人员发现抗氧化应答基因转录抑制因子BACH1具有两个加密在其同源二聚BTB结构域中的不同非传统降解信号肽（degron）。这两个degron在氧化应激条件下均被激活，并被两种互补的E3连接酶解读。

FBXO22识别由BACH1 BTB结构域二聚体界面构成的degron，该界面在氧化应激释放BACH1脱离染色质后，从转录共抑制因子中显现出来。

当该degron由于氧化作用受损时，第二个BACH1 degron通过其不稳定的BTB二聚体表现出来，并被一对FBXL17蛋白识别。这些蛋白将底物重塑为与E3连接酶结合的单体形式进行泛素化。

这些研究结果突出了蛋白质降解信号的多维性以及不同泛素连接酶在靶向相同底物时的功能互补性。

据悉，依赖于泛素的蛋白质降解通过高特异性底物识别调控多种细胞功能，这一过程依赖于泛素E3连接酶解码靶标降解信号的能力。

附：英文原文

Title: Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress

Author: Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I. James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng

Issue&Volume: 2024-11-05

Abstract: 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.

DOI: 10.1016/j.cell.2024.10.012

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01188-7