The IKK (Inhibitor of IkB kinase) complex has an essential role in the activation of the family of NF-kappaB transcription factors in response to a variety of stimuli. To identify novel IKK interacting proteins we performed an unbiased proteomics screen where we identified, transferrin receptor 1 (TFR1). TFR1 is required for transferrin binding and internalisation and ultimately in iron homeostasis. TFR1 depletion does not lead to changes in IKK subunit protein levels, however it does reduce the formation of the IKK complex, and inhibits TNF-alpha induced NF-kappaB dependent transcription. We find that in the absence of TFR1, NF-kappaB does not translocate to the nucleus efficiently, 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 TNF-alpha treatment, which is rescued by elevating the levels of RelA/NF-kappaB. Taken together these results indicate a new function for TFR1 in the control of IKK and NF-kappaB. Our data indicates that IKK-NF-kappaB responds to changes in iron within the cell.
- Inhibitor of nuclear factor κB kinase (IKK)
- Nuclear factor κB (NF-κB)
- Transferrin receptor 1 (TfR1)
- Tumour necrosis factor α (TNFα)