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Abstract：
Protein acetylation and deacetylation are key epigenetic modifications that regulate the initiation and development of several diseases. In the context of infection with Mycobacterium tuberculosis (M. tb), these processes are essential for host-pathogen interactions and immune responses. However, the specific effects of acetylation and deacetylation on cellular functions during M. tb infection are not fully understood. This study employed Tandem Mass Tag (TMT) labeling for quantitative proteomic profiling to examine the acetylproteome (acetylome) profiles of noninfected and M. tb-infected macrophages. We identified 715 acetylated peptides from 1,072 proteins and quantified 544 lysine acetylation sites (Kac) in 402 proteins in noninfected and M. tb-infected macrophages. Our research revealed a link between acetylation events and metabolic changes during M. tb infection. Notably, the deacetylation of heat shock protein 60 (HSP60), a key chaperone protein, was significantly associated with this process. Specifically, the deacetylation of HSP60 at K96 by sirtuin3 (SIRT3) enhances macrophage apoptosis, leading to the elimination of intracellular M. tb. These findings underscore the pivotal role of the SIRT3-HSP60 axis in the host immune response to M. tb. This study offers a new perspective on host protein acetylation and suggests that targeting host-directed therapies could be a promising approach for tuberculosis immunotherapy.
OBJECTIVE: Protein acetylation is crucial for the onset, development, and outcome of tuberculosis (TB). Our study comprehensively investigated the dynamics of lysine acetylation during M. tb infection, shedding light on the intricate host-pathogen interactions that underlie the pathogenesis of tuberculosis. Using an advanced quantitative lysine proteomics approach, different profiles of acetylation sites and proteins in macrophages infected with M. tb were identified. Functional enrichment and protein-protein network analyses revealed significant associations between acetylated proteins and key cellular pathways, highlighting their critical role in the host response to M. tb infection. Furthermore, the deacetylation of HSP60 and its influence on macrophage-mediated clearance of M. tb underscore the functional significance of acetylation in tuberculosis pathogenesis. In conclusion, this study provides valuable insights into the regulatory mechanisms governing host immune responses to M. tb infection and offers promising avenues for developing novel therapeutic interventions against TB.
OBJECTIVE: Protein acetylation is crucial for the onset, development, and outcome of tuberculosis (TB). Our study comprehensively investigated the dynamics of lysine acetylation during M. tb infection, shedding light on the intricate host-pathogen interactions that underlie the pathogenesis of tuberculosis. Using an advanced quantitative lysine proteomics approach, different profiles of acetylation sites and proteins in macrophages infected with M. tb were identified. Functional enrichment and protein-protein network analyses revealed significant associations between acetylated proteins and key cellular pathways, highlighting their critical role in the host response to M. tb infection. Furthermore, the deacetylation of HSP60 and its influence on macrophage-mediated clearance of M. tb underscore the functional significance of acetylation in tuberculosis pathogenesis. In conclusion, this study provides valuable insights into the regulatory mechanisms governing host immune responses to M. tb infection and offers promising avenues for developing novel therapeutic interventions against TB.
摘要：
蛋白质乙酰化和脱乙酰化是调节几种疾病的发生和发展的关键表观遗传修饰。在结核分枝杆菌感染的情况下（M.tb),这些过程对于宿主-病原体相互作用和免疫反应至关重要。然而,乙酰化和去乙酰化对M.tb感染过程中细胞功能的具体影响尚不完全清楚。这项研究采用串联质量标签（TMT）标记进行定量蛋白质组学分析，以检查未感染和M.tb感染的巨噬细胞的乙酰蛋白质组（乙酰组）谱。我们从1,072种蛋白质中鉴定了715种乙酰化肽，并在未感染和M.tb感染的巨噬细胞中的402种蛋白质中定量了544个赖氨酸乙酰化位点（Kac）。我们的研究揭示了在结核分枝杆菌感染期间乙酰化事件和代谢变化之间的联系。值得注意的是,热休克蛋白60（HSP60）的去乙酰化，一种关键的伴侣蛋白质，与这一过程密切相关。具体来说,通过sirtuin3（SIRT3）在K96处HSP60的去乙酰化增强巨噬细胞凋亡，导致细胞内结核分枝杆菌的消除。这些发现强调了SIRT3-HSP60轴在宿主对结核分枝杆菌的免疫应答中的关键作用。这项研究提供了关于宿主蛋白乙酰化的新观点，并表明靶向宿主的治疗可能是结核病免疫治疗的有希望的方法。
目的：蛋白质乙酰化对发病至关重要，发展,和结核病（TB）的结果。我们的研究全面调查了M.tb感染期间赖氨酸乙酰化的动力学，揭示了构成结核病发病机理的复杂宿主-病原体相互作用。使用先进的定量赖氨酸蛋白质组学方法，在感染M.tb的巨噬细胞中鉴定了不同的乙酰化位点和蛋白质谱。功能富集和蛋白质-蛋白质网络分析揭示了乙酰化蛋白质和关键细胞途径之间的显著关联。强调它们在宿主对结核分枝杆菌感染的反应中的关键作用。此外，HSP60的去乙酰化及其对巨噬细胞介导的M.tb清除的影响强调了乙酰化在结核病发病机制中的功能意义。总之,这项研究为控制宿主对结核分枝杆菌感染的免疫反应的调节机制提供了有价值的见解，并为开发针对结核病的新型治疗干预措施提供了有希望的途径。
目的：蛋白质乙酰化对发病至关重要，发展,和结核病（TB）的结果。我们的研究全面调查了M.tb感染期间赖氨酸乙酰化的动力学，揭示了构成结核病发病机理的复杂宿主-病原体相互作用。使用先进的定量赖氨酸蛋白质组学方法，在感染M.tb的巨噬细胞中鉴定了不同的乙酰化位点和蛋白质谱。功能富集和蛋白质-蛋白质网络分析揭示了乙酰化蛋白质和关键细胞途径之间的显著关联。强调它们在宿主对结核分枝杆菌感染的反应中的关键作用。此外，HSP60的去乙酰化及其对巨噬细胞介导的M.tb清除的影响强调了乙酰化在结核病发病机制中的功能意义。总之,这项研究为控制宿主对结核分枝杆菌感染的免疫反应的调节机制提供了有价值的见解，并为开发针对结核病的新型治疗干预措施提供了有希望的途径。
