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Survival of single positive thymocytes depends upon developmental control of RIPK1 kinase signaling by the IKK complex independent of NF-κB

  • Webb, Louise V
  • Barbarulo, Alessandro
  • Huysentruyt, Jelle
  • Vanden Berghe, Tom
  • Takahashi, Nozomi
  • Ley, Steven
  • Vandenabeele, Peter
  • Seddon, Benedict
Publication Date
Jan 01, 2019
Ghent University Institutional Archive
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NF-kappa B(nuclear factor kappa B) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-kappa B, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-kappa B transcription, had no impact upon thymocyte development. While IKK-deficient thymocytes were acutely sensitive to tumor necrosis factor (TNF)-induced cell death, Rel-deficient cells remained resistant, calling into question the importance of NF-kappa B as the IKK target required for thymocyte survival. Instead, we found that IKK controlled thymocyte survival by repressing cell-death-inducing activity of the serine/threonine kinase RIPK1. We observed that RIPK1 expression was induced during development of SP thymocytes and that IKK was required to prevent RIPK1-kinase-dependent death of SPs in vivo. Finally, we showed that IKK was required to protect Rel-deficient thymocytes from RIPK1-dependent cell death, underscoring the NF-kappa B-independent function of IKK during thymic development.

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