The transcriptional regulation of Nramp1 promoter

Abstract

Murine Nramp1 (Natural Resistance-Associated Macrophage Protein 1) encodes a bivalent-metallFe2+ transporter at the phagolysosome membrane and functions to control pathogen growth. Nramp1 is known to be upregulated by lipopolysaccharide + Interferon Gamma (LPS+IFN-I'), iron loading and redox stress; however, the direction of iron transported by Nramp1 is not known. The purpose of this study is to increase knowledge of the regulation of the TATA-Iess Nramp1 promoter by initiator element binding transcription factors, to identify the role of LPS+IFN-I', and oxidant stress (OS) and examine the effect of host-cell Nramp1 genotype on these responses. Transient transfection of Nramp1 promoter-reporter constructs demonstrated upregulation of Nramp 1 by upstream stimulatory protein 1 (USF 1) in synergy with transcription factor II-I (TFII-I), but not with c-Myc interacting zinc finger protein-l (Miz- 1). Ying yang 1 (YY1) prevented c-Myc mediated repression of Nramp1 promoter function. Mutation of the specificity protein 1 (Sp 1) binding site within the proximal Nramp1 promoter attenuated Nramp1 transcriptional responses. Oxidant stress (OS) activated Nramp1 and Spl-dependent transcriptional responses in macrophage cells. Nramp1 allele G169 increased tolerance to iron- or butathione sulphoximine-induced oxidant stress compared with cells expressing the D 169 allele. Higher basal Nramp 1 transcription was observed following transient transfection into D169 allele cells which was reduced with iron chelation. Furthermore, the transfected Nramp 1 promoter construct was more responsive to LPS+IFN-I' activation in G 169 allele cells. In conclusion, results showed that NrampJ carried a classical Inr element that functions III tandem with a consensus Sp 1 binding site. A role for Sp 1 was proposed for the activation of Nramp 1 promoter under oxidative stress. It is proposed that Nramp 1 in depleting iron from the cytosol caused a low OS response, providing an environment to facilitate a strong inflammatory response to LPS+IFN-I' signalling pathways activation.

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