Abstract
Zinc deficiency predisposes to a wide spectrum of chronic diseases. The human Zn proteome was predicted to represent about 10% of the total human proteome, reflecting the broad array of metabolic functions in which this micronutrient is known to participate. In the thyroid, Zn was reported to regulate cellular homeostasis, with a yet elusive mechanism. The Fischer Rat Thyroid Cell Line FRTL-5 cell model, derived from a Fischer rat thyroid and displaying a follicular cell phenotype, was used to investigate a possible causal relationship between intracellular Zn levels and thyroid function. A proteomic approach was applied to compare proteins expressed in Zn deficiency, obtained by treating cells with the Zn-specific chelator N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylene-diamine (TPEN), with Zn repleted cells. Quantitative proteomic analysis of whole cell protein extracts was performed using stable isotope dimethyl labelling coupled to nano-ultra performance liquid chromatography-mass spectrometry (UPLC-MS). TPEN treatment led to almost undetectable intracellular Zn, while decreasing thyroglobulin secretion. Subsequent addition of ZnSO4 fully reversed these phenotypes. Comparative proteomic analysis of Zn depleted/repleted cells identified 108 proteins modulated by either treatment. Biological process enrichment analysis identified functions involved in calcium release and the regulation of translation as the most strongly regulated processes in Zn depleted cells.
Highlights
The micronutrient zinc (Zn) is actively transported across biological membranes by lipid bound specialized transport proteins belonging to the SLC30 (ZIP) and SLC39 (ZnT) families [1]
We report the results of characterization of the Zn-related molecular and physiological phenotype of FRTL-5 cells, and a comparison between their baseline proteomic signature with the corresponding profiles in marginally Zn deficient thyroid follicular cells, as well as upon restoring intracellular Zn stores
Zn in insulin secretion has been extensively studied in pancreatic β-cells, but a broader role for this metal in endocrine tissues was proposed on the basis of the expression profile of vesicular Zn transporters associated with the secretory pathway [6,22,24]
Summary
The micronutrient zinc (Zn) is actively transported across biological membranes by lipid bound specialized transport proteins belonging to the SLC30 (ZIP) and SLC39 (ZnT) families [1]. A specific role for Zn ions has been demonstrated in several biological processes, the emerging picture is not yet exhaustive, especially in relation to pathologies, and further insights could be very helpful in the clinical setting. To identify pathways potentially affected by Zn deficiency/excess and playing important roles in disease development, we have recently performed an in silico approach which extended the known Zn proteome by including the Zn-binding protein interactome. The resulting Zn protein interaction network (ZNP) included proteins involved in several biological processes that are likely to be affected by Zn availability in health and disease, among which are protein localization and transport, as well as hormone secretion and hormone-dependent physiological processes [4]
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