Comparative Phosphoproteomics Reveals Components of Host Cell Invasion and Post-transcriptional Regulation During Francisella Infection
Year: 2013
Type: article
Abstract: 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.
Source: Molecular & Cellular Proteomics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, Battelle, Purdue University, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, Biological and Environmental Research, Pacific Northwest National Laboratory
Awards: G1063795107, G1242655424, G1756126698, G1916320680, G2629867817, G263956163, G2936749764, G2988778103, G3132759518, Targets of microRNA-132 in adult neurogenesis, G3398985920, Consortia for High-Throughput-Enabled Structural Biology Partnerships (U01), G490588625, G5193303719, G538270251, G5608475838, G5667310499, G5726405315, G6243784844, A Proteomics Research Resource for Integrative Biology, G84288863, G9000122217, G9000182343, G9000254780
OpenAlex ID: W2107718500