| First Author | Clarke SL | Year | 2006 |
| Journal | EMBO J | Volume | 25 |
| Issue | 3 | Pages | 544-53 |
| PubMed ID | 16424901 | Mgi Jnum | J:105934 |
| Mgi Id | MGI:3617043 | Doi | 10.1038/sj.emboj.7600954 |
| Citation | Clarke SL, et al. (2006) Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. EMBO J 25(3):544-53 |
| abstractText | The generally accepted role of iron-regulatory protein 1 (IRP1) in orchestrating the fate of iron-regulated mRNAs depends on the interconversion of its cytosolic aconitase and RNA-binding forms through assembly/disassembly of its Fe-S cluster, without altering protein abundance. Here, we show that IRP1 protein abundance can be iron-regulated. Modulation of IRP1 abundance by iron did not require assembly of the Fe-S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation. Phosphorylation of IRP1 at S138 favored the RNA-binding form and promoted iron-dependent degradation. However, phosphorylation at S138 was not required for degradation. Further, degradation of an S138 phosphomimetic mutant was not blocked by mutation of cluster-ligating cysteines. These findings were confirmed in mouse models with genetic defects in cytosolic Fe-S cluster assembly/disassembly. IRP1 RNA-binding activity was primarily regulated by IRP1 degradation in these animals. Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe-S cluster assembly or disassembly. |
