高强度证据表明，氧化应激损伤和炎症反应在结肠炎的发展中发挥重要作用。肿瘤抑制基因TSBF1、TRIM59是一种泛素E3连接酶，介导免疫反应。然而，TRIM59在结肠炎调控中的潜在分子功能尚不明确。在本研究中，我们确定了TRIM59作为克尔氏ECH相关蛋白1 (KEAP1) 的一个重要且新颖的内源性抑制因子，同时我们还确定了TRIM59是KEAP1的相互作用伴侣蛋白，在肠上皮细胞 (IEC)中催化其泛素化和降解。此外，特异性损失Trim59的IEC破坏了结肠代谢稳态，伴随肠道氧化应激损伤、内源性活性氧自由基（ROS）产生增加和促炎细胞因子释放的升高，显著促进急性或慢性结肠炎的进展。相反，通过腺相关病毒 (AAV) 感染诱导Trim59基因的过表达，转基因小鼠在急性或慢性结肠炎模型和体外实验中缓解结肠炎。在机制上，对于结肠炎的发生，TRIM59直接与KEAP1相互作用，促进泛素蛋白酶降解，从而激活NRF2以及其下游级联的抗氧化应激相关通路，进而促进抗氧化防御和减少组织损伤。所有这些发现阐明了TRIM59通过介导KEAP1失活和降解，在结肠炎的发展中发挥潜在作用，并可被视为该疾病治疗的治疗靶点。版权所有 © 2023. 由 Elsevier B.V. 发布。

Elevated evidence has reported the important role of oxidative stress injury and inflammatory response in the progression of colitis. Tumor Suppressor TSBF1, TRIM59, is a ubiquitin E3 ligase and mediates immune response. However, the underlying molecular function of TRIM59 on regulation of colitis is still not understood. In the current study, we identify the TRIM59 as a critical and novel endogenous suppressor of kelch-like ECH-associated protein 1 (KEAP1), and we also determine that TRIM59 is a KEAP1-interacting partner protein that catalyses its ubiquitination and degradation in intestinal epithelial cells (IEC). Moreover, IEC-specific loss of the Trim59 disrupts colon metabolic homeostasis, accompanied by intestinal oxidative stress injury, elevated endogenous reactive oxygen species (ROS) production and pro-inflammatory cytokines release, significantly promotes acute or chronic colitis progression. Conversely, transgenic mice with Trim59 overexpression by adeno-associated virus (AAV)-induced Trim59 gene therapeutics mitigates colitis in acute or chronic colitis rodent models and in vitro experiments. Mechanistically, in response to onset of colitis, TRIM59 directly interacts with KEAP1 and promotes ubiquitin-proteasome degradation, thus results in NRF2 activation and its downstream cascade anti-oxidative stress-related pathway activation, which facilitates anti-oxidant defense and reduces tissue damage. All the findings elucidated the potential role of TRIM59 in colitis progression by mediating KEAP1 deactivation and degradation, and could be considered as a therapeutic target for the treatment of such disease.Copyright © 2023. Published by Elsevier B.V.