Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis.
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.
Shi
Yanbo
Y
National Institute of Child Health and Human Development, Molecular Medicine Program, Bethesda, MD 20892, USA.
Ghosh
Manik C
MC
Tong
Wing-Hang
WH
Rouault
Tracey A
TA
D000595:Amino Acid Sequence; D013437:Carbon-Sulfur Lyases / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D021381:Protein Transport; D016415:Sequence Alignment; D013455:Sulfur / Q000378:metabolism*
D035925:Iron-Regulatory Proteins; C544445:LYRM4 protein, human; D013455:Sulfur; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D013437:Carbon-Sulfur Lyases; C080546:cysteine desulfurase