TfR1 interacts with the IKK complex and is involved in IKK-NF-kappaB signalling

Niall S. Kenneth, Sharon Mudie, Sanne Naron, Sonia Rocha

    Research output: Contribution to journalArticle

    19 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)275-284
    JournalBiochemical Journal
    Volume449
    Early online date27 Sep 2012
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    Transferrin Receptors
    NF-kappa B
    Phosphotransferases
    Protein Kinases
    Iron
    Tumor Necrosis Factor-alpha
    Genes
    Chemical activation
    Protein Subunits
    Transcription
    Transferrin
    Proteomics
    Transcriptional Activation
    Homeostasis
    Transcription Factors
    Apoptosis
    Proteins

    Keywords

    • Inhibitor of nuclear factor κB kinase (IKK)
    • Iron
    • Nuclear factor κB (NF-κB)
    • Transferrin
    • Transferrin receptor 1 (TfR1)
    • Tumour necrosis factor α (TNFα)

    Cite this

    Kenneth, Niall S. ; Mudie, Sharon ; Naron, Sanne ; Rocha, Sonia. / TfR1 interacts with the IKK complex and is involved in IKK-NF-kappaB signalling. In: Biochemical Journal. 2013 ; Vol. 449. pp. 275-284.
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    abstract = "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.",
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    TfR1 interacts with the IKK complex and is involved in IKK-NF-kappaB signalling. / Kenneth, Niall S.; Mudie, Sharon; Naron, Sanne; Rocha, Sonia.

    In: Biochemical Journal, Vol. 449, 2013, p. 275-284.

    Research output: Contribution to journalArticle

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    AU - Mudie, Sharon

    AU - Naron, Sanne

    AU - Rocha, Sonia

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    AB - 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.

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    KW - Transferrin receptor 1 (TfR1)

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