西湖大学刘自旭研究小组近日取得一项新成果。经过不懈努力，他们报道了去泛素酶依赖的转录沉默控制炎症。该研究于2025年7月3日发表于国际一流学术期刊《细胞研究》杂志上。

该课题组人员之前发现了发育沉默的SIX转录因子，这些转录因子在慢性微生物感染下的分化免疫细胞中被重新激活以控制炎症基因转录。

然而，调控这种转录沉默过程的分子机制尚不清楚。研究组报道了USP2，一种定位于核核并由炎症信号诱导的去泛素酶，在炎症条件下通过去泛素化稳定六种蛋白。因此，USP2-SIX复合体通过直接靶向基因启动子来协同控制NF-κ b介导的炎症基因转录。支持这个机制，Usp2/小鼠在H1N1感染期间表现出更高的死亡率，这一表型为6小鼠，由于危及生命的炎症介质水平升高和病理恶化。本研究建立了去泛素酶依赖的炎症反应转录控制以预防免疫病理，为对抗感染性疾病提供了新的治疗途径。

研究人员表示，转录控制对炎症的调节至关重要。虽然众所周知，诱导型转录抑制因子是通过信号依赖性转录上调重新合成的，但尚不清楚翻译后修饰机制（如去泛素化）是否也有助于这一过程。

附：英文原文

Title: Deubiquitinase-dependent transcriptional silencing controls inflammation

Author: Yi, Yuxin, Xu, Wenjie, Mi, Pengcheng, Ye, Siliang, Chen, Li, Alto, Neal M., Liu, Zixu

Issue&Volume: 2025-07-03

Abstract: Transcriptional control is crucial for the regulation of inflammation. While it is well-established that inducible transcriptional repressors are synthesized de novo through signal-dependent transcriptional upregulation, it remains unclear whether post-translational modification mechanisms, such as deubiquitination, also contribute to this process. We previously identified developmentally silenced sine oculis (SIX) transcription factors that are reactivated to control inflammatory gene transcription in differentiated immune cells under chronic microbial infections. However, the molecular mechanisms by which this transcriptional silencing process is regulated remain unclear. Here, we report that USP2, a deubiquitinase localized in the nucleus and induced by inflammatory signals, stabilizes SIX proteins through deubiquitination under inflammatory conditions. Consequently, the USP2-SIX complex acts in concert to control NF-κB-mediated inflammatory gene transcription by directly targeting gene promoters. Supporting this mechanism, Usp2/ mice exhibit higher mortality during H1N1 infections, which phenocopies Six1/ mice, attributed to elevated levels of life-threatening inflammatory mediators and exacerbated pathology. This study establishes a deubiquitinase-dependent transcriptional control of the inflammatory response to prevent immunopathology, offering new therapeutic avenues for combating infectious diseases.

DOI: 10.1038/s41422-025-01140-5

Source: https://www.nature.com/articles/s41422-025-01140-5