Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome
Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome
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DOI：
10.1038/sj.emboj.7601409
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发表时间：
2006-11-15
期刊：
影响因子：
11.4
通讯作者：
Kaplan, Jerry
中科院分区：
文献类型：
--
作者：
De Domenico, Ivana;Vaughn, Michael B.;Kaplan, Jerry
铁蛋白是一种由亚基组成的细胞质分子，这些亚基自组装成一个能够容纳多达4500个铁原子的纳米笼。储存在铁蛋白中的铁可以被动员起来供细胞内使用或从细胞中输出。铁转运蛋白（Fpn）的表达导致胞质铁的输出和铁蛋白的降解。铁蛋白介导的铁损失发生在细胞质中，并先于蛋白酶体对铁蛋白的降解。铁蛋白铁的耗竭诱导铁蛋白亚基的单泛素化。泛素化不是铁释放所必需的，但却是铁蛋白纳米笼分解所必需的，而铁蛋白纳米笼随后是蛋白酶体对铁蛋白的降解。从铁蛋白中提取铁并不需要特定的哺乳动物机制。当铁蛋白在酿酒酵母菌中表达时，铁蛋白可以从铁蛋白中去除，而酿酒酵母菌没有内源性铁蛋白。表达的铁蛋白被单泛素化并被蛋白酶体降解。泛素化缺陷的哺乳动物细胞暴露于铁螯合剂去铁胺会导致溶酶体中铁蛋白的降解，这可以通过自噬抑制剂来防止。因此，铁蛋白降解可以通过两种不同的机制发生。
Ferritin is a cytosolic molecule comprised of subunits that self-assemble into a nanocage capable of containing up to 4500 iron atoms. Iron stored within ferritin can be mobilized for use within cells or exported from cells. Expression of ferroportin (Fpn) results in export of cytosolic iron and ferritin degradation. Fpn-mediated iron loss from ferritin occurs in the cytosol and precedes ferritin degradation by the proteasome. Depletion of ferritin iron induces the monoubiquitination of ferritin subunits. Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome. Specific mammalian machinery is not required to extract iron from ferritin. Iron can be removed from ferritin when ferritin is expressed in Saccharomyces cerevisiae, which does not have endogenous ferritin. Expressed ferritin is monoubiquitinated and degraded by the proteasome. Exposure of ubiquitination defective mammalian cells to the iron chelator desferrioxamine leads to degradation of ferritin in the lysosome, which can be prevented by inhibitors of autophagy. Thus, ferritin degradation can occur through two different mechanisms.