Proteome of ubiquitin/MVB pathway: possible involvement of iron-induced ubiquitylation of transferrin receptor in lysosomal degradation
Proteome of ubiquitin/MVB pathway: possible involvement of iron-induced ubiquitylation of transferrin receptor in lysosomal degradation
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DOI：
10.1111/j.1365-2443.2011.01499.x
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发表时间：
2011-04-01
期刊：
影响因子：
2.1
通讯作者：
Fujita, Hideaki
中科院分区：
文献类型：
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作者：
Tachiyama, Ryo;Ishikawa, Daisuke;Fujita, Hideaki
膜蛋白的泛素化触发它们在质膜上的内吞作用和随后通过多泡体（MVB）的溶酶体降解。显性失活突变体SKD 1/Vps 4 B引起MVB中泛素化膜蛋白的积累。我们已经确定了22个膜蛋白，其贩运可能是由泛素化调控。其中九个，包括转铁蛋白受体（TfR），确实是泛素化和/或积累在MVB中的细胞表达突变Vps 4。虽然TfR的再循环途径和铁调节的表达得到了很好的表征，但调节TfR降解的机制在很大程度上是未知的。我们发现，过量的铁增强TfR的泛素化和降解溶酶体。可能是内源性铁螯合分子铁蛋白的表达上调，减弱了铁诱导的TfR降解。外源性引入的赖氨酸少的TfR，与野生型相比，表现出耐铁诱导的泛素化和降解，当内源性TfR，其中最肯定的异源二聚体与外源性的，被耗尽与siRNA。这些数据表明，铁诱导的TfR的泛素化和降解沿着MVB途径在生理上起着重要的作用，铁稳态。
Ubiquitylation of membrane proteins triggers their endocytosis at the plasma membrane and subsequent lysosomal degradation through multivesicular bodies (MVBs). A dominant-negative mutant SKD1/Vps4B caused an accumulation of ubiquitylated membrane proteins in MVBs. We have identified 22 membrane proteins whose trafficking is potentially regulated by ubiquitylation. Nine of them, including transferrin receptor (TfR), are indeed ubiquitylated and/or accumulated in MVBs in the cells expressing mutant Vps4. While the recycling route and iron-regulated expression of TfR are well characterized, the mechanism by which the degradation of TfR is regulated is largely unknown. We show that an excess of iron enhances both TfR's ubiquitylation and degradation in lysosomes. Probably, the up-regulated expression of ferritin, an endogenous iron-chelating molecule, attenuated the iron-induced degradation of TfR. Exogenously introduced lysine-less TfR, compared to the wild-type one, showed resistance to the iron-induced ubiquitylation and degradation, when endogenous TfR, which most certainly heterodimerizes with exogenous ones, was depleted with siRNA. These data suggest that the iron-induced ubiquitylation and degradation of TfR along with MVB pathway physiologically plays an important role in iron homeostasis.