Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during francisella infection

Ernesto S. Nakayasu, Rebecca Tempel, Xiaolu Cambronne, Vladislav A. Petyuk, Marcus B. Jones, Marina A. Gritsenko, Matthew E. Monroe, Feng Yang, Richard D. Smith, Joshua N. Adkins, Fred Heffron

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3297-3309
Number of pages13
JournalMolecular and Cellular Proteomics
Volume12
Issue number11
DOIs
StatePublished - Nov 2013

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Francisella
Tristetraprolin
Cellular Structures
Phosphorylation
Cell death
Cytokines
Phagocytosis
Cell Death
Infection
Hepatitis D
Francisella tularensis
Cell signaling
Tularemia
O Antigens
Lipid A
Intermediate Filaments
Macrophages
Immune system
Immunologic Factors
Pathogens

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during francisella infection. / Nakayasu, Ernesto S.; Tempel, Rebecca; Cambronne, Xiaolu; Petyuk, Vladislav A.; Jones, Marcus B.; Gritsenko, Marina A.; Monroe, Matthew E.; Yang, Feng; Smith, Richard D.; Adkins, Joshua N.; Heffron, Fred.

In: Molecular and Cellular Proteomics, Vol. 12, No. 11, 11.2013, p. 3297-3309.

Research output: Contribution to journalArticle

Nakayasu, ES, Tempel, R, Cambronne, X, Petyuk, VA, Jones, MB, Gritsenko, MA, Monroe, ME, Yang, F, Smith, RD, Adkins, JN & Heffron, F 2013, 'Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during francisella infection', Molecular and Cellular Proteomics, vol. 12, no. 11, pp. 3297-3309. https://doi.org/10.1074/mcp.M113.029850
Nakayasu, Ernesto S. ; Tempel, Rebecca ; Cambronne, Xiaolu ; Petyuk, Vladislav A. ; Jones, Marcus B. ; Gritsenko, Marina A. ; Monroe, Matthew E. ; Yang, Feng ; Smith, Richard D. ; Adkins, Joshua N. ; Heffron, Fred. / Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during francisella infection. In: Molecular and Cellular Proteomics. 2013 ; Vol. 12, No. 11. pp. 3297-3309.
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