title: TfR1 interacts with the IKK complex and is involved in IKK-NF-κB signalling.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, MSI/WTB/JBC Complex, Dow Street, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Niall S
authors.initials: NS
authors.lastname: Kenneth
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.forename: Sanne
authors.initials: S
authors.lastname: Naron
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism* / Q000502:physiology; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011990:Receptors, Transferrin / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D016328:NF-kappa B; D011990:Receptors, Transferrin; D007501:Iron; D051550:I-kappa B Kinase