TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
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DOI：
10.1042/bj20120625
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Rocha S
中科院分区：
文献类型：
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作者：
Kenneth NS;Mudie S;Naron S;Rocha S
IKK [NF-κB（核因子κB）激酶抑制剂]复合物在响应各种刺激激活NF-κB转录因子家族中具有重要作用。为了鉴定新的IKK相互作用蛋白，我们进行了无偏的蛋白质组学筛选，其中我们鉴定了TfR 1（转铁蛋白受体1）。TfR 1是转铁蛋白结合和内化所必需的，并最终用于铁稳态。TfR 1缺失不会导致IKK亚基蛋白水平的变化;然而，它确实会减少IKK复合物的形成，并抑制TNFα（肿瘤坏死因子α）诱导的NF-κ B依赖性转录。我们发现，在缺乏TfR 1的情况下，NF-κB不能有效地转运到细胞核，并且与靶基因启动子的结合减少，从而导致靶基因激活减少。值得注意的是，TfR 1的缺失导致TNFα处理后细胞凋亡增加，这可通过升高RelA/NF-κB水平来挽救。总而言之，这些结果表明TfR 1在控制IKK和NF-κB中具有新的功能。我们的数据表明IKK-NF-κB对细胞内铁的变化有反应。
The IKK [inhibitor of NF-κB (nuclear factor κB) kinase] complex has an essential role in the activation of the family of NF-κB transcription factors in response to a variety of stimuli. To identify novel IKK-interacting proteins, we performed an unbiased proteomics screen where we identified TfR1 (transferrin receptor 1). TfR1 is required for transferrin binding and internalization and ultimately for iron homoeostasis. TfR1 depletion does not lead to changes in IKK subunit protein levels; however, it does reduce the formation of the IKK complex, and inhibits TNFα (tumour necrosis factor α)-induced NF-κB-dependent transcription. We find that, in the absence of TfR1, NF-κB does not translocate to the nucleus efficiently, and there is a reduction in the binding to target gene promoters and consequentially less target gene activation. Significantly, depletion of TfR1 results in an increase in apoptosis in response to TNFα treatment, which is rescued by elevating the levels of RelA/NF-κB. Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-κB. Our data indicate that IKK–NF-κB responds to changes in iron within the cell.