Theileria annulata Hijacks Host Signaling: Integrated Phosphoproteomics and transcriptomics Unveils ERK1/2 as a Central Regulator of Host Transcription Factors.

IF 6.1 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS
Debabrata Dandasena, Vengatachala Moorthy A, Akash Suresh, Vasundhra Bhandari, Sonti Roy, Paresh Sharma
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引用次数: 0

Abstract

THEILERIA: transformed bovine leukocytes exhibit cancer-like characteristics, but the molecular mechanisms driving these transformations remain unclear. This study provides the first comprehensive phosphoproteomic analysis of both host and parasite in Theileria annulata-infected leukocyte cell lines. We show that T. annulata significantly induces changes in the host protein phosphorylation, impacting key cancer-related processes such as apoptosis suppression, CAMK signaling, and telomere maintenance. A pivotal finding is the parasite's manipulation of the MAPK pathway via sustained ERK1/2 activation, which regulates the phosphorylation of critical transcription factors like RUNX3, FOSL2, BCL6, c-JUN, JUNB, and c-MYC. Transcriptomic analysis of genes controlled by these transcription factors confirmed their role in T. annulata replication. ERK inhibition disrupts phosphorylation, deactivates these transcription factors, and induces apoptosis in infected cells. This underscores the ERK-AP-1 axis as a central mechanism of Theileria pathogenesis and a promising therapeutic target. Additionally, parasite-specific phosphoproteins and kinases were identified, offering new insights into therapeutic strategies to combat infection.

环孢杆菌劫持宿主信号:综合磷酸化蛋白质组学和转录组学揭示了ERK1/2作为宿主转录因子的中心调节因子。
转化的牛白细胞表现出类似癌症的特征,但驱动这些转化的分子机制尚不清楚。本研究首次对环芽孢杆菌感染的白细胞细胞系的宿主和寄生虫进行了全面的磷蛋白组学分析。我们发现环孢霉显著诱导宿主蛋白磷酸化的变化,影响关键的癌症相关过程,如细胞凋亡抑制、CAMK信号传导和端粒维持。一个关键的发现是寄生虫通过持续的ERK1/2激活来操纵MAPK通路,从而调节关键转录因子如RUNX3、FOSL2、BCL6、c-JUN、JUNB和c-MYC的磷酸化。转录组学分析证实了这些转录因子控制的基因在环孢霉复制中的作用。ERK抑制破坏磷酸化,使这些转录因子失活,并诱导感染细胞凋亡。这强调了ERK-AP-1轴作为伊氏杆菌发病的中心机制和一个有希望的治疗靶点。此外,还鉴定了寄生虫特异性磷酸化蛋白和激酶,为对抗感染的治疗策略提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular & Cellular Proteomics
Molecular & Cellular Proteomics 生物-生化研究方法
CiteScore
11.50
自引率
4.30%
发文量
131
审稿时长
84 days
期刊介绍: The mission of MCP is to foster the development and applications of proteomics in both basic and translational research. MCP will publish manuscripts that report significant new biological or clinical discoveries underpinned by proteomic observations across all kingdoms of life. Manuscripts must define the biological roles played by the proteins investigated or their mechanisms of action. The journal also emphasizes articles that describe innovative new computational methods and technological advancements that will enable future discoveries. Manuscripts describing such approaches do not have to include a solution to a biological problem, but must demonstrate that the technology works as described, is reproducible and is appropriate to uncover yet unknown protein/proteome function or properties using relevant model systems or publicly available data. Scope: -Fundamental studies in biology, including integrative "omics" studies, that provide mechanistic insights -Novel experimental and computational technologies -Proteogenomic data integration and analysis that enable greater understanding of physiology and disease processes -Pathway and network analyses of signaling that focus on the roles of post-translational modifications -Studies of proteome dynamics and quality controls, and their roles in disease -Studies of evolutionary processes effecting proteome dynamics, quality and regulation -Chemical proteomics, including mechanisms of drug action -Proteomics of the immune system and antigen presentation/recognition -Microbiome proteomics, host-microbe and host-pathogen interactions, and their roles in health and disease -Clinical and translational studies of human diseases -Metabolomics to understand functional connections between genes, proteins and phenotypes
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