Human Molecular Genetics Advance Access originally published online on May 18, 2009
Human Molecular Genetics 2009 18(16):3014-3025; doi:10.1093/hmg/ddp239
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Published by Oxford University Press 2009
Human ISD11 is essential for both iron–sulfur cluster assembly and maintenance of normal cellular iron homeostasis
National Institute of Child Health and Human Development, Molecular Medicine Program, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. Tel: +1 301 496 6368; Fax: +1 301 402 0078; Email: trou{at}helix.nih.gov
Received February 12, 2009; Revised May 6, 2009; Accepted May 15, 2009
The LYR family consists of proteins of diverse functions that contain the conserved tripeptide ‘LYR’ near the N-terminus, and it includes Isd11, which was previously observed to have an important role in iron–sulfur (Fe–S) cluster biogenesis in Saccharomyces cerevisiae. Here, we have cloned and characterized human ISD11 and shown that human ISD11 forms a stable complex in vivo with the human cysteine desulfurase (ISCS), which generates the inorganic sulfur needed for Fe–S protein biogenesis. Similar to ISCS, we have found that ISD11 localizes to the mitochondrial compartment, as expected, but also to the nucleus of mammalian cells. Using RNA-interference techniques, we have shown that suppression of human ISD11 inactivated mitochondrial and cytosolic aconitases. In addition, ISD11 suppression activated iron-responsive element-binding activity of iron regulatory protein 1, increased protein levels of iron regulatory protein 2, and resulted in abnormal punctate ferric iron accumulations in cells. These results indicate that ISD11 is important in the biogenesis of Fe–S clusters in mammalian cells, and its loss disrupts normal mitochondrial and cytosolic iron homeostasis.