Regulation of the cysteine desulfurase Nfs1 and the scaffold protein IscU in macrophages stimulated with interferon-γ and lipopolysaccharide

Biogenesis of iron-sulfur (Fe-S) clusters in mammals involves a complex mitochondrial machinery that provides inorganic sulfide and iron for their assembly and insertion into apo-proteins. Mechanisms of Fe-S cluster assembly are just being unraveled, and regulation of the genes of this machinery remains unknown. In this study, we report that expression of two essential components of the Fe-S machinery, the cysteine desulfurase Nfs1 and its scaffold protein partner IscU, is down-regulated at both mRNA and protein levels when murine macrophages are physiologically stimulated with IFN-γ and LPS. Regulation did not rely on cluster disassembly or NO production because exposure of cells to exogenous sources of NO did not alter Nfs1 expression, while it converted cytosolic Fe-S aconitase into its apo-form and because macrophages from NOS2 deficient mice displayed Nfs1 down-regulation. While IFN-γ alone induced Nfs1 protein instability, LPS triggered a delayed decline of Nfs1, rather involving transcriptional events or mRNA instability. Also, the expression of IscU was down-regulated in IFN-γ- and/or LPS-stimulated macrophages independently of NO, pointing to a general mechanism for marshalling the regulation of the Fe-S cluster assembly machinery in macrophages exposed to inflammatory stimuli.