Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China.
National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, Shandong, China.
Cell Commun Signal. 2024 Oct 18;22(1):508. doi: 10.1186/s12964-024-01887-1.
Ubiquitination functions as an important posttranslational modification for orchestrating inflammatory immune responses and cell death during pathogenic infection. The ubiquitination machinery is a major target hijacked by pathogenic bacteria to promote their survival and proliferation. Type I interferon (IFN-I) plays detrimental roles in host defense against Francisella novicida (F. novicida) infection. The effects of IFN-I on the ubiquitination of host proteins during F. novicida infection remain unclear. Herein, we delineate the dynamic ubiquitinome alterations in both wild-type (WT) and interferon-alpha receptor-deficient (Ifnar) primary bone marrow-derived macrophages (BMDMs) during F. novicida infection. Using diGly proteomics and stable isotope labeling (SILAC), we quantified ubiquitination sites in proteins from primary WT and Ifnar BMDMs with and without F. novicida infection. Our mass spectrometry analysis identified 2,491 ubiquitination sites in 1,077 endogenous proteins. Our study revealed that F. novicida infection induces dynamic changes in the ubiquitination of proteins involved in the cell death, phagocytosis, and inflammatory response pathways. IFN-I signaling is essential for both the increase and reduction in ubiquitination in response to F. novicida infection. We identified IFN-I-dependent ubiquitination in proteins involved in glycolysis and vesicle transport processes and highlighted key hub proteins modified by ubiquitination within cell death pathways. These findings underscore the significant influence of IFN-I signaling on modulating ubiquitination during F. novicida infection and provide valuable insights into the complex interplay between the host and F. novicida.
泛素化作为一种重要的翻译后修饰，在病原感染过程中协调炎症免疫反应和细胞死亡。泛素化机制是病原细菌主要劫持的目标，以促进其存活和增殖。I 型干扰素（IFN-I）在宿主防御弗朗西斯菌属 novicida（F. novicida）感染中发挥有害作用。IFN-I 对 F. novicida 感染过程中宿主蛋白泛素化的影响尚不清楚。在此，我们描述了野生型（WT）和干扰素-α受体缺陷（Ifnar）原代骨髓来源巨噬细胞（BMDMs）在 F. novicida 感染过程中动态泛素组改变。使用 diGly 蛋白质组学和稳定同位素标记（SILAC），我们定量了 F. novicida 感染前后 WT 和 Ifnar BMDMs 中蛋白质的泛素化位点。我们的质谱分析鉴定了 1077 种内源性蛋白质中的 2491 个泛素化位点。我们的研究表明，F. novicida 感染诱导参与细胞死亡、吞噬和炎症反应途径的蛋白质泛素化的动态变化。IFN-I 信号对于 F. novicida 感染后增加和减少泛素化是必需的。我们确定了 IFN-I 依赖性泛素化在参与糖酵解和囊泡运输过程的蛋白质中，并强调了细胞死亡途径中受泛素化修饰的关键枢纽蛋白。这些发现强调了 IFN-I 信号在调节 F. novicida 感染过程中泛素化的重要影响，并为宿主和 F. novicida 之间的复杂相互作用提供了有价值的见解。
