Abstract
After iron, zinc is the most abundant intracellular metal and Zni quota is maintained in a narrow range (100‐500 uM) by the activity of zinc importers (SLC39A1‐14) and zinc exporters (SLC30A1‐10). Although virtually all zinc is bound to protein, a chelatable pool of Zni is capable of participating in intracellular signaling and functions. We used chemical and genetic techniques to reveal a role for decreases in Zni to affect LPS mediated apoptosis in SPAEC. Early (0.5 to 4.0 hrs) after a proapototic dose (100 ng/ml) of LPS, we noted a decrease in Zni as revealed by the zinc sensitive fluorophore, FluoZin‐3, via FACS. Confirmation of this relative decrease after LPS was obtained via: a) EPI fluorescence microscopy in live cells that revealed a 60% decrease in Zni ; and b) 40% decrease of activity of zinc sensitive metal transcription element (MRE) fused to luciferase reporter that was previously transfected into SPAEC. The functional consequences of decreases in Zni were ascertained by: a) rescuing SPAEC from LPS induced increases in caspase 3/7 by addition of exogenous zinc to normalize potential LPS induced decreases in Zni; and b) mimicking effect of LPS on caspase 3/7 activity with zinc chelator, TPEN. We conclude that LPS results in a change in net activity of zinc transporters resulting in decrease in Zni and this decrease is an important intracellular signaling pathway transducing the apoptotic effects of LPS on SPAEC.
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