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

    • 12 Citations

    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.

    Original languageEnglish (US)
    Pages (from-to)129-143
    Number of pages15
    JournalToxicological Sciences
    Volume135
    Issue number1
    DOIs
    StatePublished - Sep 2013

    Profile

    Spleen
    Phosphorylation
    Paranasal Sinus Neoplasms
    Proteins
    Mitogen-Activated Protein Kinases
    Apoptosis
    Trichothecenes
    Isotope Labeling
    Phosphopeptides
    Gene Ontology
    Mycotoxins
    Phosphoproteins
    Lymphoid Tissue
    Lymphocyte Activation
    Biological Processes
    Titanium
    Cytoskeleton
    Phosphatidylinositol 3-Kinases
    Mast Cells
    Proteomics

    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

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

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

    Research output: Contribution to journalArticle

    @article{96729e24f139422baafe9c37c6a16a99,
    title = "Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress",
    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.",
    keywords = "Deoxynivalenol, Phosphorylation, Quantitative proteomics, Ribotoxic stress response, Trichothecene mycotoxin",
    author = "Xiao Pan and Whitten, {Douglas A.} and Ming Wu and Christina Chan and Wilkerson, {Curtis G.} and Pestka, {James J.}",
    year = "2013",
    month = "9",
    doi = "10.1093/toxsci/kft145",
    volume = "135",
    pages = "129--143",
    journal = "Toxicological Sciences",
    issn = "1096-6080",
    publisher = "Oxford University Press",
    number = "1",

    }

    TY - JOUR

    T1 - Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress

    AU - Pan,Xiao

    AU - Whitten,Douglas A.

    AU - Wu,Ming

    AU - Chan,Christina

    AU - Wilkerson,Curtis G.

    AU - Pestka,James J.

    PY - 2013/9

    Y1 - 2013/9

    N2 - 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.

    AB - 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.

    KW - Deoxynivalenol

    KW - Phosphorylation

    KW - Quantitative proteomics

    KW - Ribotoxic stress response

    KW - Trichothecene mycotoxin

    UR - http://www.scopus.com/inward/record.url?scp=84883144809&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84883144809&partnerID=8YFLogxK

    U2 - 10.1093/toxsci/kft145

    DO - 10.1093/toxsci/kft145

    M3 - Article

    VL - 135

    SP - 129

    EP - 143

    JO - Toxicological Sciences

    T2 - Toxicological Sciences

    JF - Toxicological Sciences

    SN - 1096-6080

    IS - 1

    ER -