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

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 si...

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Bibliographic Details
Main Authors: Brenner, Dirk (Author) , Golks, Alexander (Author) , Krammer, Peter H. (Author) , Arnold, Rüdiger (Author)
Format: Article (Journal)
Language:English
Published: 8 December 2005
In: The EMBO journal
Year: 2005, Volume: 24, Issue: 24, Pages: 4279-4290
ISSN:1460-2075
DOI:10.1038/sj.emboj.7600894
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/sj.emboj.7600894
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.1038/sj.emboj.7600894
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Author Notes:Dirk Brenner, Alexander Golks, Friedemann Kiefer, Peter H Krammer, Rüdiger Arnold
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Summary: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 T cells. We show that HPK1 is a functional component of the endogenous I?B kinase (IKK) complex and is crucial for TCR-mediated NF?B activation. While full-length HPK1 enhances IKK? phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF?B 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 NF?B upon TCR restimulation by binding to IKKα and IKK?. 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 NF?B, and propose that HPK1 is a life/death switch in T lymphocytes.
Item Description:Gesehen am 04.03.2021
Physical Description:Online Resource
ISSN:1460-2075
DOI:10.1038/sj.emboj.7600894

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