Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death

Dirk Brenner, Alexander Golks, Friedemann Kiefer, Peter H. Krammer, Rüdiger Arnold*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

57 Citations (Scopus)


Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary Tcells. We show that HPK1 is a functional component of the endogenous IκB kinase (IKK) complex and is crucial for TCR-mediated NFκB activation. While full-length HPK1 enhances IKKβ phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NFκB activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NFκB upon TCR restimulation by binding to IKKα and IKKβ. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NFκB, and propose that HPK1 is a life/death switch in T lymphocytes.

Original languageEnglish
Pages (from-to)4279-4290
Number of pages12
JournalEMBO Journal
Issue number24
Publication statusPublished - 21 Dec 2005
Externally publishedYes


  • AICD
  • Apoptosis
  • IKK
  • Signaling
  • TCR


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