Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Science (Impact Factor: 33.61). 09/2009; 326(5953):718-21. DOI: 10.1126/science.1176333
Source: PubMed


Eukaryotic cells require iron for survival and have developed regulatory mechanisms for maintaining appropriate intracellular
iron concentrations. The degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathway,
but the E3 ubiquitin ligase responsible for its proteolysis has remained elusive. We found that a SKP1-CUL1-FBXL5 ubiquitin
ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate
adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like
domain in its N terminus. Thus, iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular
iron levels through the stability and activity of FBXL5.

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    • "The acquisition of this (4Fe-4S) cluster converts IRP1 into a cytosolic aconitase, and thus IRP1's conversion to the ISC-containing form is dependent on active ISC biogenesis in the mitochondria and/or the cytosol[109]. IRP2 is unable to acquire an ISC[111], and it is instead regulated at the level of protein abundance by proteasomal degradation via the IRP2-targeting E3 ubiquitin ligase subunit, F-box and leucine-rich repeat protein 5 (FBXL5); a protein which itself is regulated at the level of protein stability by iron and oxygen[112,113]. For recent reviews of the IRP/IRE system in iron homeostasis, see114115116. "
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    • "In vitro analyses suggest that BTS interacts with (Fig. 3) and restricts the accumulation of iron-responsive bHLH transcription factors ILR3 and bHLH115 through its E3 ligase activity and can mediate proteasomal degradation of these targets even in the absence of HHE domains (Fig. 5, A–C). Notably, the mammalian protein FBXL5, unlike BTS, does not contain a RING domain and thus lacks the ability to directly ubiquitinate its targets for degradation via the 26S proteasome pathway (Salahudeen et al., 2009; Vashisht et al., 2009; Thompson et al., 2012). FBXL5 does, however, provide the specificity to the SCF FBXL5 E3 ligase complex to regulate iron homeostasis. "
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    • "This allows proteasomal degradation of FBXL5, which leads to concomitant accumulation of IRP2. Interestingly, FBXL5 can also promote the ubiquitination and degradation of IRP1 mutants that cannot form a 4Fe-4S cluster (Salahudeen et al., 2009; Vashisht et al., 2009). Proteasomal degradation of wild type apo-IRP1 under conditions of impairment of the iron-sulfur cluster assembly pathway has been proposed to operate as a reserve mechanism to control the IRE-binding activity of IRP1 (Clarke et al., 2006; Wang et al., 2007). "
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