IRON-DEPENDENT OXIDATION, UBIQUITINATION, AND DEGRADATION OF IRON REGULATORY PROTEIN-2 - IMPLICATIONS FOR DEGRADATION OF OXIDIZED PROTEINS

The ability of iron to catalyze formation of reactive oxygen species s ignificantly contributes to its toxicity In cells and animals. Iron up take and distribution is regulated tightly in mammalian cells, in part by iron regulatory protein 2 (IRP2), a protein that is degraded effic iently by the proteasome in iron-replete cells. Here, me demonstrate t hat IRP2 is oxidized and ubiquitinated in cells before degradation. Mo reover, iron-dependent oxidation converts IRP2 into a substrate for ub iquitination in vitro. A regulatory pathway is described in which exce ss iron is sensed by its ability to catalyze site-specific oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated IRP2 subseq uently is degraded by the proteasome, Selective targeting and removal of oxidatively modified proteins may contribute to the turnover of man y proteins that are degraded by the proteasome.