期刊
EMBO JOURNAL
卷 25, 期 3, 页码 544-553出版社
WILEY
DOI: 10.1038/sj.emboj.7600954
关键词
Fe-S protein; iron homeostasis; iron-regulatory protein 1; phosphorylation; protein degradation
资金
- NIA NIH HHS [AG16998] Funding Source: Medline
- NIDDK NIH HHS [DK47219, R01 DK062474, T32 DK007665, T32 DK07665, DK62474] Funding Source: Medline
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.
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