Abstract
The involvement of macrophages (Mvarphis) as host, accessory, and effector cells in the development of infectious diseases, together with their central role in iron homeostasis, place these immune cells as key players in the interface between iron and infection. Having previously shown that the functional expression of NRAMP-1 results in increased protein phosphorylation mediated in part by an iron-dependent inhibition of Mvarphi protein-tyrosine phosphatase (PTP) activity, we sought to study the mechanism(s) underlying this specific event. Herein we have identified the mononuclear dicitrate iron complex [Fe(cit)(2)H(4-x)]((1+x)-) as the species responsible for the specific inhibition of Mvarphi PTP activity. By using biochemical and computational approaches, we show that [Fe(cit)(2)](5-) targets the catalytic pocket of the PTP SHP-1, competitively inhibiting its interaction with an incoming phosphosubstrate. In vitro and in vivo inhibition of PTP activity by iron-citrate results in protein hyperphosphorylation and enhanced MAPK signaling in response to LPS stimulation. We propose that iron-citrate-mediated PTP inhibition represents a novel and biologically relevant regulatory mechanism of signal transduction.
Highlights
The balance of protein phosphorylation, maintained by the concerted action of protein kinases and protein phosphatases, is fundamental in determining the outcome of multiple cellular functions ranging from cell proliferation to cell death [1]
We have recently reported that functional expression of NRAMP-1 results in lower M protein tyrosine phosphatases (PTPs) activity and increased protein phosphorylation, in part explaining the pleiotropic effects of NRAMP-1 [15]
Iron-dependent PTP Inhibition Is Specific to Iron-Citrate Chelates—Having previously observed that Fe-cit strongly inhibits PTP activity in vitro [15], we investigated whether different iron donors excreted a similar effect
Summary
The balance of protein phosphorylation, maintained by the concerted action of protein kinases and protein phosphatases, is fundamental in determining the outcome of multiple cellular functions ranging from cell proliferation to cell death [1]. We have identified the mononuclear dicitrate iron complex [Fe(cit)2H4-x](1؉x)؊ as the species responsible for the specific inhibition of M PTP activity.
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