Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress

Xiao Pan, Douglas A. Whitten, Ming Wu, Christina Chan, Curtis G. Wilkerson, James J. Pestka

Research output: Contribution to journalArticle

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Abstract

The trichothecene mycotoxin deoxynivalenol (DON) targets the innate immune system and is of public health significance because of its frequent presence in human and animal food. DON-induced proinflammatory gene expression and apoptosis in the lymphoid tissue have been associated with a ribotoxic stress response (RSR) that involves rapid phosphorylation of mitogen-activated protein kinases (MAPKs). To better understand the relationship between protein phosphorylation and DON's immunotoxic effects, stable isotope dimethyl labeling-based proteomics in conjunction with titanium dioxide chromatography was employed to quantitatively profile the immediate (≤ 30 min) phosphoproteome changes in the spleens of mice orally exposed to 5 mg/kg body weight DON. A total of 90 phosphoproteins indicative of novel phosphorylation events were significantly modulated by DON. In addition to critical branches and scaffolds of MAPK signaling being affected, DON exposure also altered phosphorylation of proteins that mediate phosphatidylinositol 3-kinase/AKT pathways. Gene ontology analysis revealed that DON exposure affected biological processes such as cytoskeleton organization, regulation of apoptosis, and lymphocyte activation and development, which likely contribute to immune dysregulation associated with DON-induced RSR. Consistent with these findings, DON impacted phosphorylation of proteins within diverse immune cell populations, including monocytes, macrophages, T cells, B cells, dendritic cells, and mast cells. Fuzzy c-means clustering analysis further indicated that DON evoked several distinctive temporal profiles of regulated phosphopeptides. Overall, the findings from this investigation can serve as a template for future focused exploration and modeling of cellular responses associated with the immunotoxicity evoked by DON and other ribotoxins.

LanguageEnglish (US)
Pages129-143
Number of pages15
JournalToxicological Sciences
Volume135
Issue number1
DOIs
StatePublished - Sep 2013

Profile

Spleen
Phosphorylation
Mitogen-Activated Protein Kinases
deoxynivalenol
Phosphatidylinositol 3-Kinase
Trichothecenes
Apoptosis
Isotope Labeling
Biological Phenomena
Phosphopeptides
Gene Ontology
Proteins
T-cells
Lymphocytes
Mycotoxins
Macrophages
Immune system
Phosphoproteins
Lymphoid Tissue
Public health

Keywords

  • Deoxynivalenol
  • Phosphorylation
  • Quantitative proteomics
  • Ribotoxic stress response
  • Trichothecene mycotoxin

ASJC Scopus subject areas

  • Toxicology

Cite this

Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress. / Pan, Xiao; Whitten, Douglas A.; Wu, Ming; Chan, Christina; Wilkerson, Curtis G.; Pestka, James J.

In: Toxicological Sciences, Vol. 135, No. 1, 09.2013, p. 129-143.

Research output: Contribution to journalArticle

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