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Dugast E.,French Institute of Health and Medical Research | Dugast E.,University of Nantes | Dugast E.,Institute Of Recherche En Transplantation | Kiss-Toth E.,University of Sheffield | And 26 more authors.
Journal of Biological Chemistry | Year: 2013

In a previous study, we identified TRIB1, a serine-threonine kinase-like molecule, as a biomarker of chronic antibody-mediated rejection of human kidneys when measured in peripheral blood mononuclear cells. Here, we focused our analysis on a specific subset of peripheral blood mononuclear cells that play a dominant role in regulating immune responses in health and disease, so-called CD4+CD25+Foxp3+ regulatory T cells (Tregs). We isolated both human and murine Treg and non- Treg counterparts and analyzed TRIB1 and Foxp3 mRNA expression by quantitative PCR on the freshly isolated cells or following 24 h of activation. Physical interaction between the human TRIB1 and Foxp3 proteins was analyzed in live cell lines by protein complementation assay using both flow cytometry and microscopy and confirmed in primary freshly isolated human CD4+CD25hiCD127 -Tregs by co-immunoprecipitation. Both TRIB1 and Foxp3 were expressed at significantly higher levels in Tregs than in their CD4+CD25 - counterparts (p < 0.001). Moreover, TRIB1 and Foxp3 mRNA levels correlated tightly in Tregs (Spearman r = 1.0; p < 0.001, n = 7), but not in CD4+CD25- T cells. The protein complementation assay revealed a direct physical interaction between TRIB1 and Foxp3 in live cells. This interaction was impaired upon deletion of the TRIB1 N-terminal but not the C-terminal domain, suggesting an interaction in the nucleus. This direct interaction within the nucleus was confirmed in primary human Tregs by co-immunoprecipitation. These data show a direct relationship between TRIB1 and Foxp3 in terms of their expression and physical interaction and highlight Tribbles-1 as a novel binding partner of Foxp3 in Tregs. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Dugast E.,French Institute of Health and Medical Research | Kiss-Toth E.,University of Sheffield | Soulillou J.-P.,French Institute of Health and Medical Research | Soulillou J.-P.,Institute Of Recherche En Transplantation | And 5 more authors.
Current Molecular Medicine | Year: 2013

This review describes the key role of the serine-threonine kinase like protein Tribbles-1 in health as well as in diverse human pathologies. Tribbles-1 is a homolog protein of the Drosophila Tribbles. In Drosophila, the Tribbles protein is involved in the cell-cycle progression during mitosis and in mammals initial data showed TRIB1 to be involved in cell proliferation. In mammals, TRIB1 lacks a catalytic domain and thus acts as an adaptor protein by interacting with several partners. The activity of TRIB1 seems to be very specific to the environment and the cells type in which it is expressed, and a role for this molecule has been mainly described in several pathological states including various cancers such as acute myeloid leukemia and ovarian cancer. Further evidence has also linked TRIB1 to the control of plasmalipid homeostasis thus indicating the role of this molecule as a risk factor for myocardial infarction. Finally, TRIB1 is shown to be up-regulated during inflammatory events such as chronic inflammation of atherosclerotic arteries or chronic antibody-mediated rejection of transplanted organs. Here we provide a review of the current state of the scientific literature for TRIB1, highlighting its role in diverse pathologies and inflammatory states. A better understanding of the role of this protein as both a target as well as a biological marker in diseases should drive the development of new therapeutic strategies. © 2013 Bentham Science Publishers.

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