Comparative Phosphoproteomics Reveals Components of Host Cell Invasion and Post-transcriptional Regulation During Francisella Infection
| Autor: | Ernesto S. Nakayasu, Vladislav A. Petyuk, Fred Heffron, Marcus B. Jones, Joshua N. Adkins, Xiaolu A. Cambronne, Matthew E. Monroe, Feng Yang, Richard D. Smith, Rebecca Tempel, Marina A. Gritsenko |
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| Rok vydání: | 2013 |
| Předmět: |
Proteomics
Cell signaling Tristetraprolin Biology Biochemistry Cell Line Analytical Chemistry Tularemia Mice Immune system medicine Animals Protein Interaction Maps Francisella RNA Processing Post-Transcriptional Molecular Biology Francisella tularensis Innate immune system Virulence Research Macrophages Intracellular parasite Phosphoproteins biology.organism_classification medicine.disease Immunity Innate Cell biology Mice Inbred C57BL Genes Bacterial Host-Pathogen Interactions Mutation Cytokines RNA Female Gram-Negative Bacterial Infections |
| Zdroj: | Molecular & Cellular Proteomics. 12:3297-3309 |
| ISSN: | 1535-9476 |
| DOI: | 10.1074/mcp.m113.029850 |
| Popis: | Francisella tularensis is a facultative intracellular bacterium that causes the deadly disease tularemia. Most evidence suggests that Francisella is not well recognized by the innate immune system that normally leads to cytokine expression and cell death. In previous work, we identified new bacterial factors that were hyper-cytotoxic to macrophages. Four of the identified hyper-cytotoxic strains (lpcC, manB, manC, and kdtA) had an impaired lipopolysaccharide (LPS) synthesis and produced an exposed lipid A lacking the O-antigen. These mutants were not only hyper-cytotoxic but also were phagocytosed at much higher rates compared with the wild type parent strain. To elucidate the cellular signaling underlying this enhanced phagocytosis and cell death, we performed a large-scale comparative phosphoproteomic analysis of cells infected with wild-type and delta-lpcC F. novicida. Our data suggest that not only actin but also intermediate filaments and microtubules are important for F. novicida entry into the host cells. In addition, we observed differential phosphorylation of tristetraprolin, a key component of the mRNA-degrading machinery that controls the expression of a variety of genes including many cytokines. Infection with the delta-lpcC mutant induced the hyper-phosphorylation and inhibition of tristetraprolin, leading to the production of cytokines such as IL-1beta and TNF-alpha that may kill the host cells by triggering apoptosis. Together, our data provide new insights for Francisella invasion and a post-transcriptional mechanism that prevents the expression of host immune response factors that control infection by this pathogen. |
| Databáze: | OpenAIRE |
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